101 results on '"Barozzi I"'
Search Results
2. Genetic and pharmacological characterization of patient-derived bladder cancer cell models for novel therapeutic target identification
- Author
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Herek, P., primary, Grubb, E., additional, Ertl, I.E., additional, Lemberger, U., additional, Gutmann, M., additional, Vician, P., additional, Barozzi, I., additional, Batlogg, K., additional, Shariat, S.F., additional, Berger, W., additional, and Englinger, B., additional
- Published
- 2023
- Full Text
- View/download PDF
3. Cis-regulatory architecture and functions of a gene desert controlling pleiotropic expression and cardiac pacemaker development
- Author
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Osterwalder, M, primary, Abassah-Oppong, S, additional, Mannion, B, additional, Rouco, R, additional, Zoia, M, additional, Roland, V, additional, Barozzi, I, additional, Lopez-Rios, J, additional, Andrey, G, additional, Visel, A, additional, Pennacchio, L, additional, and Cobb, J, additional
- Published
- 2022
- Full Text
- View/download PDF
4. Author Correction: Perspectives on ENCODE (Nature, (2020), 583, 7818, (693-698), 10.1038/s41586-020-2449-8)
- Author
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Abascal, FBC, Acosta, R, Addleman, NJ, Adrian, J, Afzal, V, Aken, B, Ai, R, Akiyama, JA, Jammal, OA, Amrhein, H, Anderson, SM, Dileep, V, Ding, B, Djebali, S, Dobin, A, Dominguez, D, Donaldson, S, Drenkow, J, Dreszer, TR, Snyder, MP, Drier, Y, Duff, MO, Dunn, D, Sisu, C, Eastman, C, Ecker, JR, Edwards, MD, El-Ali, N, Andrews, GR, Antoshechkin, I, Ardlie, KG, Armstrong, J, Astley, M, Banerjee, B, Barkal, AA, Barnes, IHA, Barozzi, I, Barrell, D, Barson, G, Bates, D, Baymuradov, UK, Bazile, C, Beer, MA, Beik, S, Bender, MA, Bennett, R, Bouvrette, LPB, Bernstein, BE, Berry, A, Bhaskar, A, Bignell, A, Blue, SM, Bodine, DM, Boix, C, Boley, N, Borrman, T, Borsari, B, Boyle, AP, Brandsmeier, LA, Breschi, A, Bresnick, EH, Brooks, JA, Buckley, M, Burge, CB, Byron, R, Cahill, E, Cai, L, Cao, L, Carty, M, Castanon, RG, Castillo, A, Chaib, H, Chan, ET, Chee, DR, Chee, S, Chen, H, Chen, JY, Chen, S, Cherry, JM, Chhetri, SB, Choudhary, JS, Chrast, J, Chung, D, Clarke, D, Cody, NAL, Coppola, CJ, Coursen, J, D’Ippolito, AM, Dalton, S, Danyko, C, Davidson, C, Davila-Velderrain, J, Davis, CA, Dekker, J, Deran, A, DeSalvo, G, Despacio-Reyes, G, Dewey, CN, Dickel, DE, Diegel, M, Diekhans, M, and The ENCODE Project Consortium
- Abstract
The Original Article (https://doi.org/10.1038/s41586-020-2449-8) was published on 29 July 2020. Copyright © The Authors 2022. In this Article, the authors Rizi Ai (Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA) and Shantao Li (Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA) were mistakenly omitted from the ENCODE Project Consortium author list. The original Article has been corrected online.
- Published
- 2022
5. The co-evolution of the genome and epigenome in colorectal cancer
- Author
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Heide, T, Househam, J, Cresswell, G, Spiteri, I, Lynn, C, Mossner, M, Kimberley, C, Fernandez-Mateos, J, Chen, B, Zapata, L, James, C, Barozzi, I, Chkhaidze, K, Nichol, D, Gunasri, V, Berner, A, Schmidt, M, Lakatos, E, Baker, A, Costa, H, Mitchinson, M, Piazza, R, Jansen, M, Caravagna, G, Ramazzotti, D, Shibata, D, Bridgewater, J, Rodriguez-Justo, M, Magnani, L, Graham, T, Sottoriva, A, Heide, Timon, Househam, Jacob, Cresswell, George D., Spiteri, Inmaculada, Lynn, Claire, Mossner, Maximilian, Kimberley, Chris, Fernandez-Mateos, Javier, Chen, Bingjie, Zapata, Luis, James, Chela, Barozzi, Iros, Chkhaidze, Ketevan, Nichol, Daniel, Gunasri, Vinaya, Berner, Alison, Schmidt, Melissa, Lakatos, Eszter, Baker, Ann-Marie, Costa, Helena, Mitchinson, Miriam, Piazza, Rocco, Jansen, Marnix, Caravagna, Giulio, Ramazzotti, Daniele, Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Graham, Trevor A., Sottoriva, Andrea, Heide, T, Househam, J, Cresswell, G, Spiteri, I, Lynn, C, Mossner, M, Kimberley, C, Fernandez-Mateos, J, Chen, B, Zapata, L, James, C, Barozzi, I, Chkhaidze, K, Nichol, D, Gunasri, V, Berner, A, Schmidt, M, Lakatos, E, Baker, A, Costa, H, Mitchinson, M, Piazza, R, Jansen, M, Caravagna, G, Ramazzotti, D, Shibata, D, Bridgewater, J, Rodriguez-Justo, M, Magnani, L, Graham, T, Sottoriva, A, Heide, Timon, Househam, Jacob, Cresswell, George D., Spiteri, Inmaculada, Lynn, Claire, Mossner, Maximilian, Kimberley, Chris, Fernandez-Mateos, Javier, Chen, Bingjie, Zapata, Luis, James, Chela, Barozzi, Iros, Chkhaidze, Ketevan, Nichol, Daniel, Gunasri, Vinaya, Berner, Alison, Schmidt, Melissa, Lakatos, Eszter, Baker, Ann-Marie, Costa, Helena, Mitchinson, Miriam, Piazza, Rocco, Jansen, Marnix, Caravagna, Giulio, Ramazzotti, Daniele, Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Graham, Trevor A., and Sottoriva, Andrea
- Abstract
Colorectal malignancies are a leading cause of cancer-related death1and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4–7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.
- Published
- 2022
6. UP16 - Genetic and pharmacological characterization of patient-derived bladder cancer cell models for novel therapeutic target identification
- Author
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Herek, P., Grubb, E., Ertl, I.E., Lemberger, U., Gutmann, M., Vician, P., Barozzi, I., Batlogg, K., Shariat, S.F., Berger, W., and Englinger, B.
- Published
- 2023
- Full Text
- View/download PDF
7. Author Correction: Expanded encyclopaedias of DNA elements in the human and mouse genomes
- Author
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Moore, JE, Abascal, F, Acosta, R, Addleman, NJ, Adrian, J, Afzal, V, Aken, B, Akiyama, JA, Jammal, OA, Amrhein, H, Anderson, SM, Edwards, MD, El-Ali, N, Elhajjajy, SI, Andrews, GR, Antoshechkin, I, Ardlie, KG, Armstrong, J, Astley, M, Banerjee, B, Barkal, AA, Barnes, IHA, Barozzi, I, Barrell, D, Barson, G, Bates, D, Baymuradov, UK, Bazile, C, Beer, MA, Beik, S, Bender, MA, Bennett, R, Bouvrette, LPB, Bernstein, BE, Berry, A, Bhaskar, A, Bignell, A, Blue, SM, Bodine, DM, Boix, C, Boley, N, Borrman, T, Borsari, B, Boyle, AP, Brandsmeier, LA, Breschi, A, Bresnick, EH, Brooks, JA, Buckley, M, Burge, CB, Byron, R, Cahill, E, Cai, L, Cao, L, Carty, M, Castanon, RG, Castillo, A, Chaib, H, Chan, ET, Chee, DR, Chee, S, Chen, H, Chen, JY, Chen, S, Cherry, JM, Chhetri, SB, Choudhary, JS, Chrast, J, Chung, D, Clarke, D, Cody, NAL, Coppola, CJ, Coursen, J, D’Ippolito, AM, Dalton, S, Danyko, C, Davidson, C, Davila-Velderrain, J, Davis, CA, Dekker, J, Deran, A, DeSalvo, G, Despacio-Reyes, G, Dewey, CN, Dickel, DE, Diegel, M, Diekhans, M, Dileep, V, Ding, B, Djebali, S, Dobin, A, Dominguez, D, Donaldson, S, Drenkow, J, Dreszer, TR, Drier, Y, Duff, MO, Dunn, D, Eastman, C, Ecker, JR, and The ENCODE Project Consortium
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Multidisciplinary ,epigenomics ,data integration ,functional genomics - Abstract
Online Correction for: https://doi.org/10.1038/s41586-020-2493-4 | Erratum for https://bura.brunel.ac.uk/handle/2438/21299 In the version of this article initially published, two members of the ENCODE Project Consortium were missing from the author list. Rizi Ai (Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA) and Shantao Li (Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA) are now included in the author list. These errors have been corrected in the online version of the article : 'Expanded encyclopaedias of DNA elements in the human and mouse genomes'. https://www.nature.com/articles/s41586-021-04226-3 https://www.nature.com/articles/s41586-021-04226-3
- Published
- 2022
- Full Text
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8. Genome-wide mapping of Myc binding and gene regulation in serum-stimulated fibroblasts
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Perna, D, Fagà, G, Verrecchia, A, Gorski, M M, Barozzi, I, Narang, V, Khng, J, Lim, K C, Sung, W-K, Sanges, R, Stupka, E, Oskarsson, T, Trumpp, A, Wei, C-L, Müller, H, and Amati, B
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- 2012
- Full Text
- View/download PDF
9. Perspectives on ENCODE
- Author
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Snyder, MP, Gingeras, TR, Abascal, F, Acosta, R, Addleman, NJ, Adrian, J, Afzal, V, Aken, B, Akiyama, JA, Jammal, OA, Amrhein, H, Dileep, V, Ding, B, Djebali, S, Dobin, A, Dominguez, D, Sisu, C, Donaldson, S, Drenkow, J, Dreszer, TR, Drier, Y, Duff, MO, Dunn, D, Anderson, SM, Andrews, GR, Eastman, C, Ecker, JR, Edwards, MD, El-Ali, N, Elhajjajy, SI, Antoshechkin, I, Ardlie, KG, Armstrong, J, Astley, M, Banerjee, B, Barkal, AA, Barnes, IHA, Barozzi, I, Barrell, D, Barson, G, Bates, D, Baymuradov, UK, Bazile, C, Beer, MA, Beik, S, Bender, MA, Bennett, R, Bouvrette, LPB, Bernstein, BE, Berry, A, Bhaskar, A, Bignell, A, Blue, SM, Bodine, DM, Boix, C, Boley, N, Borrman, T, Borsari, B, Boyle, AP, Brandsmeier, LA, Breschi, A, Bresnick, EH, Brooks, JA, Buckley, M, Burge, CB, Byron, R, Cahill, E, Cai, L, Cao, L, Carty, M, Castanon, RG, Castillo, A, Chaib, H, Chan, ET, Chee, DR, Chee, S, Chen, H, Chen, JY, Chen, S, Cherry, JM, Chhetri, SB, Choudhary, JS, Chrast, J, Chung, D, Clarke, D, Cody, NAL, Coppola, CJ, Coursen, J, D’Ippolito, AM, Dalton, S, Danyko, C, Davidson, C, Davila-Velderrain, J, Davis, CA, Dekker, J, Deran, A, DeSalvo, G, Despacio-Reyes, G, Dewey, CN, Dickel, DE, Diegel, M, Diekhans, M, and The ENCODE Project Consortium
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Epigenomics ,Quality Control ,610 Medicine & health ,Computational biology ,Biology ,Regulatory Sequences, Nucleic Acid ,ENCODE ,Genome ,Histones ,03 medical and health sciences ,transcriptomics ,Mice ,0302 clinical medicine ,Databases, Genetic ,Animals ,Humans ,Transcriptomics ,Gene ,genome ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Multidisciplinary ,Binding Sites ,Genome, Human ,Molecular Sequence Annotation ,Genomics ,DNA Methylation ,Chromatin ,DNA binding site ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Perspective ,epigenomics ,Human genome ,Epigenetics ,epigenetic ,Transcription Factors - Abstract
The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression1. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community., The authors summarize the history of the ENCODE Project, the achievements of ENCODE 1 and ENCODE 2, and how the new data generated and analysed in ENCODE 3 complement the previous phases.
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- 2019
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- View/download PDF
10. Abstract ES4-2: Single cell transcriptomics reveals multi-step adaptations to endocrine therapy
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Magnani, L, primary, Barozzi, I, additional, and Hong, S, additional
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- 2020
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11. PO-355 Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer
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Magnani, L., primary, Patten, D., additional, Corleone, G., additional, Perone, Y., additional, Slaven, N., additional, Barozzi, I., additional, Coombes, C., additional, and Pruneri, G., additional
- Published
- 2018
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12. Transcription of Mammalian cis-Regulatory Elements Is Restrained by Actively Enforced Early Termination
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Austenaa, L, Barozzi, I, Simonatto, M, Masella, S, Della Chiara, G, Ghisletti, S, Curina, A, de Wit, E, Bouwman, B, de Pretis, S, Piccolo, V, Termanini, A, Prosperini, E, Pelizzola, M, de Laat, W, Natoli, G, Austenaa LMI, Barozzi I, Simonatto M, Masella S, Della Chiara G, Ghisletti S, Curina A, de Wit E, Bouwman BAM, de Pretis S, Piccolo V, Termanini A, Prosperini E, Pelizzola M, de Laat W, Natoli G, Austenaa, L, Barozzi, I, Simonatto, M, Masella, S, Della Chiara, G, Ghisletti, S, Curina, A, de Wit, E, Bouwman, B, de Pretis, S, Piccolo, V, Termanini, A, Prosperini, E, Pelizzola, M, de Laat, W, Natoli, G, Austenaa LMI, Barozzi I, Simonatto M, Masella S, Della Chiara G, Ghisletti S, Curina A, de Wit E, Bouwman BAM, de Pretis S, Piccolo V, Termanini A, Prosperini E, Pelizzola M, de Laat W, and Natoli G
- Abstract
Upon recruitment to active enhancers and promoters, RNA polymerase II (Pol II) generates short non-coding transcripts of unclear function. The mechanisms that control the length and the amount of ncRNAs generated by cis-regulatory elements are largely unknown. Here, we show that the adaptor protein WDR82 and its associated complexes actively limit such non-coding transcription. WDR82 targets the SET1 H3K4 methyltransferases and the nuclear protein phosphatase 1 (PP1) complexes to the initiating Pol II. WDR82 and PP1 also interact with components of the transcriptional termination and RNA processing machineries. Depletion of WDR82, SET1, or the PP1 subunit required for its nuclear import caused distinct but overlapping transcription termination defects at highly expressed genes and active enhancers and promoters, thus enabling the increased synthesis of unusually long ncRNAs. These data indicate that transcription initiated from cis-regulatory elements is tightly coordinated with termination mechanisms that impose the synthesis of short RNAs. Upon recruitment to enhancers and promoters, RNA polymerase II synthesizes short and poorly abundant non-coding transcripts.
- Published
- 2015
13. Functional characterisation of somatic regulatory mutations in CTCF binding sites
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N, Slaven, Barozzi I, Corleone G, SP, Hong, Sottoriva A, Patten D, A, Barry, Russello S, Patel K, and Magnani L
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- 2017
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14. Transcript dynamics of proinflammatory genes revealed by sequence analysis of subcellular RNA fractions
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Bhatt DM, Pandya-Jones A, Tong AJ, Barozzi I, Lissner MM, Natoli G, Black DL, and Smale ST
- Published
- 2012
15. Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer
- Author
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Chiaradonna, F, Barozzi, I, Miccolo, C, Bucci, G, Palorini, R, Fornasari, L, Botrugno, O, Pruneri, G, Masullo, M, Passafaro, A, Galimberti, V, Fantin, V, Richon, V, Pece, S, Viale, G, Di Fiore, P, Draetta, G, Pelicci, P, Minucci, S, Chiocca, S, CHIARADONNA, FERDINANDO, PALORINI, ROBERTA, FORNASARI, LORENZO, Chiocca, S., Chiaradonna, F, Barozzi, I, Miccolo, C, Bucci, G, Palorini, R, Fornasari, L, Botrugno, O, Pruneri, G, Masullo, M, Passafaro, A, Galimberti, V, Fantin, V, Richon, V, Pece, S, Viale, G, Di Fiore, P, Draetta, G, Pelicci, P, Minucci, S, Chiocca, S, CHIARADONNA, FERDINANDO, PALORINI, ROBERTA, FORNASARI, LORENZO, and Chiocca, S.
- Abstract
Aims: Vorinostat (suberoylanilide hydroxamic acid; SAHA) is a histone deacetylase inhibitor (HDACi) approved in the clinics for the treatment of T-cell lymphoma and with the potential to be effective also in breast cancer. We investigated the responsiveness to SAHA in human breast primary tumors and cancer cell lines. Results: We observed a differential response to drug treatment in both human breast primary tumors and cancer cell lines. Gene expression analysis of the breast cancer cell lines revealed that genes involved in cell adhesion and redox pathways, especially glutathione metabolism, were differentially expressed in the cell lines resistant to SAHA compared with the sensitive ones, indicating their possible association with drug resistance mechanisms. Notably, such an association was also observed in breast primary tumors. Indeed, addition of buthionine sulfoximine (BSO), a compound capable of depleting cellular glutathione, significantly enhanced the cytotoxicity of SAHA in both breast cancer cell lines and primary breast tumors. Innovation: We identify and validate transcriptional differences in genes involved in redox pathways, which include potential predictive markers of sensitivity to SAHA. Conclusion: In breast cancer, it could be relevant to evaluate the expression of antioxidant genes that may favor tumor resistance as a factor to consider for potential clinical application and treatment with epigenetic drugs (HDACis).
- Published
- 2015
16. Genome-wide mapping of Myc binding and gene regulation in serum-stimulated fibroblasts
- Author
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Perna, D, primary, Fagà, G, additional, Verrecchia, A, additional, Gorski, M M, additional, Barozzi, I, additional, Narang, V, additional, Khng, J, additional, Lim, K C, additional, Sung, W-K, additional, Sanges, R, additional, Stupka, E, additional, Oskarsson, T, additional, Trumpp, A, additional, Wei, C-L, additional, Müller, H, additional, and Amati, B, additional
- Published
- 2011
- Full Text
- View/download PDF
17. Analysis of the Spi1 cistrome in mouse macrophages
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Barozzi, I, primary
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18. Fish the ChIPs: a pipeline for automated genomic annotation of ChIP-Seq data
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Minucci Saverio, Termanini Alberto, Barozzi Iros, and Natoli Gioacchino
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Biology (General) ,QH301-705.5 - Abstract
Abstract Background High-throughput sequencing is generating massive amounts of data at a pace that largely exceeds the throughput of data analysis routines. Here we introduce Fish the ChIPs (FC), a computational pipeline aimed at a broad public of users and designed to perform complete ChIP-Seq data analysis of an unlimited number of samples, thus increasing throughput, reproducibility and saving time. Results Starting from short read sequences, FC performs the following steps: 1) quality controls, 2) alignment to a reference genome, 3) peak calling, 4) genomic annotation, 5) generation of raw signal tracks for visualization on the UCSC and IGV genome browsers. FC exploits some of the fastest and most effective tools today available. Installation on a Mac platform requires very basic computational skills while configuration and usage are supported by a user-friendly graphic user interface. Alternatively, FC can be compiled from the source code on any Unix machine and then run with the possibility of customizing each single parameter through a simple configuration text file that can be generated using a dedicated user-friendly web-form. Considering the execution time, FC can be run on a desktop machine, even though the use of a computer cluster is recommended for analyses of large batches of data. FC is perfectly suited to work with data coming from Illumina Solexa Genome Analyzers or ABI SOLiD and its usage can potentially be extended to any sequencing platform. Conclusions Compared to existing tools, FC has two main advantages that make it suitable for a broad range of users. First of all, it can be installed and run by wet biologists on a Mac machine. Besides it can handle an unlimited number of samples, being convenient for large analyses. In this context, computational biologists can increase reproducibility of their ChIP-Seq data analyses while saving time for downstream analyses. Reviewers This article was reviewed by Gavin Huttley, George Shpakovski and Sarah Teichmann.
- Published
- 2011
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19. Exploiting evolutionary steering to induce collateral drug sensitivity in cancer
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Javier Fernández-Mateos, Andrea Sottoriva, Carlo C. Maley, Inmaculada Spiteri, Udai Banerji, Benjamin Werner, Ahmet Acar, Mark Stubbs, Luca Magnani, Sung Pil Hong, Giulio Caravagna, Adam Stewart, Nicholas A. Trahearn, Daniel Nichol, Nicola Valeri, Georgios Vlachogiannis, Rosemary Burke, George D. Cresswell, Iros Barozzi, Acar, A., Nichol, D., Fernandez-Mateos, J., Cresswell, G. D., Barozzi, I., Hong, S. P., Trahearn, N., Spiteri, I., Stubbs, M., Burke, R., Stewart, A., Caravagna, G., Werner, B., Vlachogiannis, G., Maley, C. C., Magnani, L., Valeri, N., Banerji, U., and Sottoriva, A.
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0301 basic medicine ,Lung Neoplasms ,EGFR BLOCKADE ,Stochastic Processe ,TUMOR HETEROGENEITY ,Drug Resistance ,General Physics and Astronomy ,Drug resistance ,Pyridone ,Genome informatics ,Somatic evolution in cancer ,Antineoplastic Agent ,0302 clinical medicine ,TARGETED THERAPY ,Theoretical ,Models ,lcsh:Science ,Stochastic modelling ,media_common ,Pyrimidinone ,education.field_of_study ,Multidisciplinary ,Gefitinib ,3. Good health ,Multidisciplinary Sciences ,030220 oncology & carcinogenesis ,Science & Technology - Other Topics ,Molecular Medicine ,Lung cancer ,medicine.drug ,Human ,Drug ,Genotype ,Evolution ,Pyridones ,media_common.quotation_subject ,Science ,CELL LUNG-CANCER ,Population ,COMPETITION ,Antineoplastic Agents ,Computational biology ,Pyrimidinones ,Biology ,Clonal Evolution ,Computational Biology ,Computer Simulation ,Humans ,Models, Theoretical ,Stochastic Processes ,Drug Resistance, Neoplasm ,Evolution, Molecular ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,medicine ,Sensitivity (control systems) ,Evolutionary dynamics ,education ,Science & Technology ,MUTATIONS ,Cancer ,Molecular ,General Chemistry ,medicine.disease ,Lung Neoplasm ,030104 developmental biology ,COPY NUMBER ,Computer modelling ,Neoplasm ,lcsh:Q ,INHIBITORS ,ACQUIRED-RESISTANCE - Abstract
Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using ‘evolutionary steering’ to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108–109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance., Evolutionary steering uses therapies to control tumour evolution by exploiting trade-offs. Here, using a barcoding approach applied to large cell populations, the authors explore evolutionary steering in lung cancer cells treated with EGFR inhibitors.
- Published
- 2020
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20. The co-evolution of the genome and epigenome in colorectal cancer
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Timon Heide, Jacob Househam, George D. Cresswell, Inmaculada Spiteri, Claire Lynn, Maximilian Mossner, Chris Kimberley, Javier Fernandez-Mateos, Bingjie Chen, Luis Zapata, Chela James, Iros Barozzi, Ketevan Chkhaidze, Daniel Nichol, Vinaya Gunasri, Alison Berner, Melissa Schmidt, Eszter Lakatos, Ann-Marie Baker, Helena Costa, Miriam Mitchinson, Rocco Piazza, Marnix Jansen, Giulio Caravagna, Daniele Ramazzotti, Darryl Shibata, John Bridgewater, Manuel Rodriguez-Justo, Luca Magnani, Trevor A. Graham, Andrea Sottoriva, Heide, Timon, Househam, Jacob, Cresswell, George D, Spiteri, Inmaculada, Lynn, Claire, Mossner, Maximilian, Kimberley, Chri, Fernandez-Mateos, Javier, Chen, Bingjie, Zapata, Lui, James, Chela, Barozzi, Iro, Chkhaidze, Ketevan, Nichol, Daniel, Gunasri, Vinaya, Berner, Alison, Schmidt, Melissa, Lakatos, Eszter, Baker, Ann-Marie, Costa, Helena, Mitchinson, Miriam, Piazza, Rocco, Jansen, Marnix, Caravagna, Giulio, Ramazzotti, Daniele, Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Graham, Trevor A, Sottoriva, Andrea, Heide, T, Househam, J, Cresswell, G, Spiteri, I, Lynn, C, Mossner, M, Kimberley, C, Fernandez-Mateos, J, Chen, B, Zapata, L, James, C, Barozzi, I, Chkhaidze, K, Nichol, D, Gunasri, V, Berner, A, Schmidt, M, Lakatos, E, Baker, A, Costa, H, Mitchinson, M, Piazza, R, Jansen, M, Caravagna, G, Ramazzotti, D, Shibata, D, Bridgewater, J, Rodriguez-Justo, M, Magnani, L, Graham, T, and Sottoriva, A
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Adenoma ,Multidisciplinary ,Epigenomic ,Genome, Human ,Tumour heterogeneity ,Oncogenes ,colorectal cancer genomics ,Colorectal cancer ,Cancer genomic ,Chromatin ,Epigenome ,Cell Transformation, Neoplastic ,Mutation ,Humans ,Interferons ,Colorectal Neoplasms ,Computational biology and bioinformatic ,Transcription Factors - Abstract
Colorectal malignancies are a leading cause of cancer-related death1 and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4–7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.
- Published
- 2022
21. The Histone Methyltransferase Wbp7 Controls Macrophage Function through GPI Glycolipid Anchor Synthesis
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Liv Austenaa, Elena Prosperini, Renato Ostuni, A. Francis Stewart, Giuseppe Testa, Gioacchino Natoli, Iros Barozzi, Agnieszka Chronowska, Alberto Termanini, Austenaa, L, Barozzi, I, Chronowska, A, Termanini, A, Ostuni, R, Prosperini, E, Stewart, Af, Testa, G, and Natoli, G
- Subjects
Lipopolysaccharides ,Glycosylphosphatidylinositols ,CD14 ,Immunology ,Lipopolysaccharide Receptors ,Biology ,Histones ,Cell membrane ,Mice ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,Gene expression ,medicine ,Animals ,Transferase ,Immunology and Allergy ,Cells, Cultured ,030304 developmental biology ,Mice, Knockout ,chemistry.chemical_classification ,0303 health sciences ,Macrophages ,Cell Membrane ,Membrane Proteins ,Histone-Lysine N-Methyltransferase ,medicine.anatomical_structure ,Enzyme ,Infectious Diseases ,Hexosyltransferases ,Biochemistry ,chemistry ,030220 oncology & carcinogenesis ,Histone methyltransferase ,Histone Methyltransferases ,lipids (amino acids, peptides, and proteins) ,Myeloid-Lymphoid Leukemia Protein ,Intracellular ,Signal Transduction - Abstract
Summary Histone methyltransferases catalyze site-specific deposition of methyl groups, enabling recruitment of transcriptional regulators. In mammals, trimethylation of lysine 4 in histone H3, a modification localized at the transcription start sites of active genes, is catalyzed by six enzymes (SET1a and SET1b, MLL1–MLL4) whose specific functions are largely unknown. By using a genomic approach, we found that in macrophages, MLL4 (also known as Wbp7) was required for the expression of Pigp, an essential component of the GPI-GlcNAc transferase, the enzyme catalyzing the first step of glycosylphosphatidylinositol (GPI) anchor synthesis. Impaired Pigp expression in Wbp7 −/− macrophages abolished GPI anchor-dependent loading of proteins on the cell membrane. Consistently, loss of GPI-anchored CD14, the coreceptor for lipopolysaccharide (LPS) and other bacterial molecules, markedly attenuated LPS-triggered intracellular signals and gene expression changes. These data link a histone-modifying enzyme to a biosynthetic pathway and indicate a specialized biological role for Wbp7 in macrophage function and antimicrobial response.
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- 2012
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22. Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer
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Salvatore Pece, Gabriele Bucci, Pier Paolo Di Fiore, Oronza A. Botrugno, Pier Giuseppe Pelicci, Iros Barozzi, Valeria Fantin, Saverio Minucci, Giancarlo Pruneri, Viviana Galimberti, Roberta Palorini, Alfonso Passafaro, Ferdinando Chiaradonna, Claudia Miccolo, Victoria M. Richon, Lorenzo Fornasari, Giuseppe Viale, Giulio Draetta, Susanna Chiocca, Michele Masullo, Chiaradonna, F, Barozzi, I, Miccolo, C, Bucci, G, Palorini, R, Fornasari, L, Botrugno, O, Pruneri, G, Masullo, M, Passafaro, A, Galimberti, V, Fantin, V, Richon, V, Pece, S, Viale, G, Di Fiore, P, Draetta, G, Pelicci, P, Minucci, S, and Chiocca, S
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Physiology ,medicine.drug_class ,Clinical Biochemistry ,Primary Cell Culture ,Antineoplastic Agents ,Breast Neoplasms ,Biology ,Pharmacology ,Hydroxamic Acids ,Biochemistry ,chemistry.chemical_compound ,Breast cancer ,Cell Line, Tumor ,medicine ,Humans ,Buthionine sulfoximine ,Epigenetics ,Cytotoxicity ,Molecular Biology ,Vorinostat ,Buthionine Sulfoximine ,General Environmental Science ,Cell Proliferation ,Forum Original Research CommunicationsHistone Deacetylases (S. Chiocca, Ed.) ,Cell growth ,Histone deacetylase inhibitor ,Cell Biology ,medicine.disease ,Lymphoma ,Gene Expression Regulation, Neoplastic ,Histone Deacetylase Inhibitors ,chemistry ,Drug Resistance, Neoplasm ,General Earth and Planetary Sciences ,Female ,Oxidation-Reduction ,medicine.drug - Abstract
Aims: Vorinostat (suberoylanilide hydroxamic acid; SAHA) is a histone deacetylase inhibitor (HDACi) approved in the clinics for the treatment of T-cell lymphoma and with the potential to be effective also in breast cancer. We investigated the responsiveness to SAHA in human breast primary tumors and cancer cell lines. Results: We observed a differential response to drug treatment in both human breast primary tumors and cancer cell lines. Gene expression analysis of the breast cancer cell lines revealed that genes involved in cell adhesion and redox pathways, especially glutathione metabolism, were differentially expressed in the cell lines resistant to SAHA compared with the sensitive ones, indicating their possible association with drug resistance mechanisms. Notably, such an association was also observed in breast primary tumors. Indeed, addition of buthionine sulfoximine (BSO), a compound capable of depleting cellular glutathione, significantly enhanced the cytotoxicity of SAHA in both breast cancer cell lines and primary breast tumors. Innovation: We identify and validate transcriptional differences in genes involved in redox pathways, which include potential predictive markers of sensitivity to SAHA. Conclusion: In breast cancer, it could be relevant to evaluate the expression of antioxidant genes that may favor tumor resistance as a factor to consider for potential clinical application and treatment with epigenetic drugs (HDACis). Antioxid. Redox Signal. 23, 15–29.
- Published
- 2015
23. A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance
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Leonie A. Cluse, Geoffrey M. Matthews, Isabella Pallavicini, Ricky W. Johnstone, Simona Moretti, Lucia Altucci, Oronza A. Botrugno, Susanna Chiocca, Saverio Minucci, Iros Barozzi, Lorenzo Fornasari, Pier Giuseppe Pelicci, Silvia Senese, Roberto Dal Zuffo, Fabio Santoro, Santoro, F, Botrugno, Oa, Dal Zuffo, R, Pallavicini, I, Matthews, Gm, Cluse, L, Barozzi, I, Senese, S, Fornasari, L, Moretti, S, Altucci, Lucia, Pelicci, Pg, Chiocca, S, Johnstone, Rw, and Minucci, S.
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Acute promyelocytic leukemia ,Male ,Transgene ,Immunology ,Blotting, Western ,Histone Deacetylase 2 ,Histone Deacetylase 1 ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Real-Time Polymerase Chain Reaction ,Biochemistry ,Genomic Instability ,Mice ,Leukemia, Promyelocytic, Acute ,medicine ,Tumor Cells, Cultured ,Animals ,RNA, Messenger ,Progenitor cell ,RNA, Small Interfering ,neoplasms ,Cell Proliferation ,Leukemia ,Oncogene ,Reverse Transcriptase Polymerase Chain Reaction ,Valproic Acid ,Cell Differentiation ,Cell Biology ,Hematology ,medicine.disease ,Flow Cytometry ,HDAC1 ,Histone Deacetylase Inhibitors ,Mice, Inbred C57BL ,Survival Rate ,Haematopoiesis ,tumorigenesis ,Cell Transformation, Neoplastic ,embryonic structures ,Cancer research ,Female ,Stem cell ,Tumor Suppressor Protein p53 ,Carcinogenesis - Abstract
Aberrant recruitment of histone deacetylases (HDACs) by the oncogenic fusion protein PML-RAR is involved in the pathogenesis of acute promyelocytic leukemia (APL). PML-RAR, however, is not sufficient to induce disease in mice but requires additional oncogenic lesions during the preleukemic phase. Here, we show that knock-down of Hdac1 and Hdac2 dramatically accelerates leukemogenesis in transgenic preleukemic mice. These events are not restricted to APL because lymphomagenesis driven by deletion of p53 or, to a lesser extent, by c-myc overexpression, was also accelerated by Hdac1 knock-down. In the preleukemic phase of APL, Hdac1 counteracts the activity of PML-RAR in (1) blocking differentiation; (2) impairing genomic stability; and (3) increasing self-renewal in hematopoietic progenitors, as all of these events are affected by the reduction in Hdac1 levels. This led to an expansion of a subpopulation of PML-RAR-expressing cells that is the major source of leukemic stem cells in the full leukemic stage. Remarkably, short-term treatment of preleukemic mice with an HDAC inhibitor accelerated leukemogenesis. In contrast, knock-down of Hdac1 in APL mice led to enhanced survival duration of the leukemic animals. Thus, Hdac1 has a dual role in tumorigenesis: oncosuppressive in the early stages, and oncogenic in established tumor cells.
- Published
- 2013
24. Latent enhancers activated by stimulation in differentiated cells
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Alessia Curina, Serena Ghisletti, Iros Barozzi, Renato Ostuni, Elena Prosperini, Viviana Piccolo, Alberto Termanini, Sara Polletti, Silvia Bonifacio, Gioacchino Natoli, Ostuni, R, Piccolo, V, Barozzi, I, Polletti, S, Termanini, A, Bonifacio, S, Curina, A, Prosperini, E, Ghisletti, S, and Natoli, G.
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Regulation of gene expression ,Genetics ,0303 health sciences ,biology ,Biochemistry, Genetics and Molecular Biology(all) ,Cellular differentiation ,Enhancer RNAs ,Stimulation ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,Histone ,030220 oncology & carcinogenesis ,biology.protein ,Histone code ,Enhancer ,Transcription factor ,030304 developmental biology - Abstract
SummaryAccording to current models, once the cell has reached terminal differentiation, the enhancer repertoire is completely established and maintained by cooperatively acting lineage-specific transcription factors (TFs). TFs activated by extracellular stimuli operate within this predetermined repertoire, landing close to where master regulators are constitutively bound. Here, we describe latent enhancers, defined as regions of the genome that in terminally differentiated cells are unbound by TFs and lack the histone marks characteristic of enhancers but acquire these features in response to stimulation. Macrophage stimulation caused sequential binding of stimulus-activated and lineage-determining TFs to these regions, enabling deposition of enhancer marks. Once unveiled, many of these enhancers did not return to a latent state when stimulation ceased; instead, they persisted and mediated a faster and stronger response upon restimulation. We suggest that stimulus-specific expansion of the cis-regulatory repertoire provides an epigenomic memory of the exposure to environmental agents.
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- 2013
25. Age-dependent differences in breast tumor microenvironment: challenges and opportunities for efficacy studies in preclinical models.
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Falvo P, Gruener S, Orecchioni S, Pisati F, Talarico G, Mitola G, Lombardi D, Bravetti G, Winkler J, Barozzi I, and Bertolini F
- Abstract
Immunity suffers a function deficit during aging, and the incidence of cancer is increased in the elderly. However, most cancer models employ young mice, which are poorly representative of adult cancer patients. We have previously reported that Triple-Therapy (TT), involving antigen-presenting-cell activation by vinorelbine and generation of TCF1
+ -stem-cell-like T cells (scTs) by cyclophosphamide significantly improved anti-PD-1 efficacy in anti-PD1-resistant models like Triple-Negative Breast Cancer (TNBC) and Non-Hodgkin's Lymphoma (NHL), due to T-cell-mediated tumor killing. Here, we describe the effect of TT on TNBC growth and on tumor-microenvironment (TME) of young (6-8w, representative of human puberty) versus adult (12 m, representative of 40y-humans) mice. TT-efficacy was similar in young and adults, as CD8+ scTs were only marginally reduced in adults. However, single-cell analyses revealed major differences in the TME: adults had fewer CD4+ scTs, B-naïve and NK-cells, and more memory-B-cells. Cancer-associated-fibroblasts (CAF) with an Extracellular Matrix (ECM) deposition-signature (Matrix-CAFs) were more common in young mice, while pro-inflammatory stromal populations and myofibroblasts were more represented in adults. Matrix-CAFs in adult mice displayed decreased ECM-remodeling abilities, reduced collagen deposition, and a different pattern of interactions with the other cells of the TME. Taken together, our results suggest that age-dependent differences in the TME should be considered when designing preclinical studies., Competing Interests: Competing interests: The authors have declared that no conflict of interest exists. Ethics: Experiments involving animals were approved by the Italian Ministry of Health and have been done in accordance with the applicable Italian laws (D.L.vo 26/14 and following amendments), the Institutional Animal Care and Use Committee, and the institutional guidelines at the European Institute of Oncology, following ARRIVE guidelines (projects 267/2020 and 219/2024)., (© 2025. The Author(s).)- Published
- 2025
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26. A gene desert required for regulatory control of pleiotropic Shox2 expression and embryonic survival.
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Abassah-Oppong S, Zoia M, Mannion BJ, Rouco R, Tissières V, Spurrell CH, Roland V, Darbellay F, Itum A, Gamart J, Festa-Daroux TA, Sullivan CS, Kosicki M, Rodríguez-Carballo E, Fukuda-Yuzawa Y, Hunter RD, Novak CS, Plajzer-Frick I, Tran S, Akiyama JA, Dickel DE, Lopez-Rios J, Barozzi I, Andrey G, Visel A, Pennacchio LA, Cobb J, and Osterwalder M
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- Animals, Humans, Mice, Morphogenesis, Enhancer Elements, Genetic, Gene Expression Regulation, Developmental, Homeodomain Proteins genetics, Homeodomain Proteins metabolism
- Abstract
Approximately a quarter of the human genome consists of gene deserts, large regions devoid of genes often located adjacent to developmental genes and thought to contribute to their regulation. However, defining the regulatory functions embedded within these deserts is challenging due to their large size. Here, we explore the cis-regulatory architecture of a gene desert flanking the Shox2 gene, which encodes a transcription factor indispensable for proximal limb, craniofacial, and cardiac pacemaker development. We identify the gene desert as a regulatory hub containing more than 15 distinct enhancers recapitulating anatomical subdomains of Shox2 expression. Ablation of the gene desert leads to embryonic lethality due to Shox2 depletion in the cardiac sinus venosus, caused in part by the loss of a specific distal enhancer. The gene desert is also required for stylopod morphogenesis, mediated via distributed proximal limb enhancers. In summary, our study establishes a multi-layered role of the Shox2 gene desert in orchestrating pleiotropic developmental expression through modular arrangement and coordinated dynamics of tissue-specific enhancers., (© 2024. The Author(s).)
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- 2024
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27. A Functional Survey of the Regulatory Landscape of Estrogen Receptor-Positive Breast Cancer Evolution.
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Barozzi I, Slaven N, Canale E, Lopes R, Amorim Monteiro Barbosa I, Bleu M, Ivanoiu D, Pacini C, Mensa' E, Chambers A, Bravaccini S, Ravaioli S, Győrffy B, Dieci MV, Pruneri G, Galli GG, and Magnani L
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- Humans, Female, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm genetics, Antineoplastic Agents, Hormonal therapeutic use, Antineoplastic Agents, Hormonal pharmacology, Breast Neoplasms genetics, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Receptors, Estrogen metabolism
- Abstract
Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer, potentially explaining ∼40% of relapses. If other mechanisms underlie the evolution of hormone-dependent breast cancer under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CRE) to cancer evolution by focusing on 12 megabases of noncoding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of noncoding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies trigger the emergence of transient features which could ultimately be exploited to hinder the adaptive process. Significance: This study shows that cells adapting to endocrine therapies undergo changes in the usage or regulatory regions. Dormant cells are less vulnerable to regulatory perturbation but gain transient dependencies which can be exploited to decrease the formation of dormant persisters., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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28. Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells.
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Rosano D, Sofyali E, Dhiman H, Ghirardi C, Ivanoiu D, Heide T, Vingiani A, Bertolotti A, Pruneri G, Canale E, Dewhurst HF, Saha D, Slaven N, Barozzi I, Li T, Zemlyanskiy G, Phillips H, James C, Győrffy B, Lynn C, Cresswell GD, Rehman F, Noberini R, Bonaldi T, Sottoriva A, and Magnani L
- Subjects
- Humans, Female, Neoplasm Recurrence, Local genetics, Gene Expression Regulation, Neoplastic, Breast Neoplasms genetics, Breast Neoplasms pathology, Breast Neoplasms drug therapy, Epigenesis, Genetic
- Abstract
Patients with estrogen receptor-positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled a rare cohort treated with long-term neoadjuvant ETs until progression. Next, we developed an in vitro evolutionary study to record the adaptive strategies of individual lineages in unperturbed parallel experiments. Our data demonstrate that ETs induce nongenetic cell state transitions into dormancy in a stochastic subset of cells via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably in the absence of recurrent genetic alterations. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs., Significance: This study advances the understanding of therapy-induced dormancy with potential clinical implications for breast cancer. Estrogen receptor-positive breast cancer cells adapt to endocrine treatment by entering a dormant state characterized by strong heterochromatinization with no recurrent genetic changes. Targeting the epigenetic rewiring impairs the adaptation of cancer cells to ETs. See related commentary by Llinas-Bertran et al., p. 704. This article is featured in Selected Articles from This Issue, p. 695., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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29. Tumor-Extrinsic Axl Expression Shapes an Inflammatory Microenvironment Independent of Tumor Cell Promoting Axl Signaling in Hepatocellular Carcinoma.
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Breitenecker K, Heiden D, Demmer T, Weber G, Primorac AM, Hedrich V, Ortmayr G, Gruenberger T, Starlinger P, Herndler-Brandstetter D, Barozzi I, and Mikulits W
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- Animals, Mice, Humans, Epithelial-Mesenchymal Transition genetics, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Mice, Knockout, Receptor Protein-Tyrosine Kinases metabolism, Receptor Protein-Tyrosine Kinases genetics, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Axl Receptor Tyrosine Kinase, Tumor Microenvironment, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins genetics, Liver Neoplasms metabolism, Liver Neoplasms pathology, Liver Neoplasms genetics, Signal Transduction
- Abstract
The activation of the receptor tyrosine kinase Axl by Gas6 is a major driver of tumorigenesis. Despite recent insights, tumor cell-intrinsic and -extrinsic Axl functions are poorly understood in hepatocellular carcinoma (HCC). Thus, we analyzed the cell-specific aspects of Axl in liver cancer cells and in the tumor microenvironment. We show that tumor-intrinsic Axl expression decreased the survival of mice and elevated the number of pulmonary metastases in a model of resection-based tumor recurrence. Axl expression increased the invasion of hepatospheres by the activation of Akt signaling and a partial epithelial-to-mesenchymal transition (EMT). However, the liver tumor burden of Axl
+/+ mice induced by diethylnitrosamine plus carbon tetrachloride was reduced compared to systemic Axl-/- mice. Tumors of Axl+/+ mice were highly infiltrated with cytotoxic cells, suggesting a key immune-modulatory role of Axl. Interestingly, hepatocyte-specific Axl deficiency did not alter T cell infiltration, indicating that these changes are independent of tumor cell-intrinsic Axl. In this context, we observed an upregulation of multiple chemokines in Axl+/+ compared to Axl-/- tumors, correlating with HCC patient data. In line with this, Axl is associated with a cytotoxic immune signature in HCC patients. Together these data show that tumor-intrinsic Axl expression fosters progression, while tumor-extrinsic Axl expression shapes an inflammatory microenvironment.- Published
- 2024
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30. Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer.
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Di Chiaro P, Nacci L, Arco F, Brandini S, Polletti S, Palamidessi A, Donati B, Soriani C, Gualdrini F, Frigè G, Mazzarella L, Ciarrocchi A, Zerbi A, Spaggiari P, Scita G, Rodighiero S, Barozzi I, Diaferia GR, and Natoli G
- Subjects
- Humans, Extracellular Matrix genetics, Extracellular Matrix metabolism, Extracellular Matrix pathology, Basement Membrane metabolism, Nervous System, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal pathology
- Abstract
Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion., Competing Interests: Declaration of interests L.M. reports research funding from Bristol-Myers Squibb and Roche, and consulting fees from Tethis, which are all unrelated to the content of this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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31. Increased enhancer-promoter interactions during developmental enhancer activation in mammals.
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Chen Z, Snetkova V, Bower G, Jacinto S, Clock B, Dizehchi A, Barozzi I, Mannion BJ, Alcaina-Caro A, Lopez-Rios J, Dickel DE, Visel A, Pennacchio LA, and Kvon EZ
- Subjects
- Animals, Mice, Promoter Regions, Genetic genetics, Transcriptional Activation genetics, Chromatin genetics, Enhancer Elements, Genetic genetics, Mammals genetics
- Abstract
Remote enhancers are thought to interact with their target promoters via physical proximity, yet the importance of this proximity for enhancer function remains unclear. Here we investigate the three-dimensional (3D) conformation of enhancers during mammalian development by generating high-resolution tissue-resolved contact maps for nearly a thousand enhancers with characterized in vivo activities in ten murine embryonic tissues. Sixty-one percent of developmental enhancers bypass their neighboring genes, which are often marked by promoter CpG methylation. The majority of enhancers display tissue-specific 3D conformations, and both enhancer-promoter and enhancer-enhancer interactions are moderately but consistently increased upon enhancer activation in vivo. Less than 14% of enhancer-promoter interactions form stably across tissues; however, these invariant interactions form in the absence of the enhancer and are likely mediated by adjacent CTCF binding. Our results highlight the general importance of enhancer-promoter physical proximity for developmental gene activation in mammals., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2024
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32. Dynamic enhancer landscapes in human craniofacial development.
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Rajderkar SS, Paraiso K, Amaral ML, Kosicki M, Cook LE, Darbellay F, Spurrell CH, Osterwalder M, Zhu Y, Wu H, Afzal SY, Blow MJ, Kelman G, Barozzi I, Fukuda-Yuzawa Y, Akiyama JA, Afzal V, Tran S, Plajzer-Frick I, Novak CS, Kato M, Hunter RD, von Maydell K, Wang A, Lin L, Preissl S, Lisgo S, Ren B, Dickel DE, Pennacchio LA, and Visel A
- Subjects
- Humans, Animals, Mice, Gene Expression Profiling, Genomics, Protein Processing, Post-Translational, Regulatory Sequences, Nucleic Acid, Chromatin genetics
- Abstract
The genetic basis of human facial variation and craniofacial birth defects remains poorly understood. Distant-acting transcriptional enhancers control the fine-tuned spatiotemporal expression of genes during critical stages of craniofacial development. However, a lack of accurate maps of the genomic locations and cell type-resolved activities of craniofacial enhancers prevents their systematic exploration in human genetics studies. Here, we combine histone modification, chromatin accessibility, and gene expression profiling of human craniofacial development with single-cell analyses of the developing mouse face to define the regulatory landscape of facial development at tissue- and single cell-resolution. We provide temporal activity profiles for 14,000 human developmental craniofacial enhancers. We find that 56% of human craniofacial enhancers share chromatin accessibility in the mouse and we provide cell population- and embryonic stage-resolved predictions of their in vivo activity. Taken together, our data provide an expansive resource for genetic and developmental studies of human craniofacial development., (© 2024. The Author(s).)
- Published
- 2024
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33. Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes.
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Company C, Schmitt MJ, Dramaretska Y, Serresi M, Kertalli S, Jiang B, Yin JA, Aguzzi A, Barozzi I, and Gargiulo G
- Subjects
- Animals, Humans, Mice, Promoter Regions, Genetic genetics, Gene Expression, Biomarkers, Gene Expression Regulation, DNA
- Abstract
Descriptive data are rapidly expanding in biomedical research. Instead, functional validation methods with sufficient complexity remain underdeveloped. Transcriptional reporters allow experimental characterization and manipulation of developmental and disease cell states, but their design lacks flexibility. Here, we report logical design of synthetic cis-regulatory DNA (LSD), a computational framework leveraging phenotypic biomarkers and trans-regulatory networks as input to design reporters marking the activity of selected cellular states and pathways. LSD uses bulk or single-cell biomarkers and a reference genome or custom cis-regulatory DNA datasets with user-defined boundary regions. By benchmarking validated reporters, we integrate LSD with a computational ranking of phenotypic specificity of putative cis-regulatory DNA. Experimentally, LSD-designed reporters targeting a wide range of cell states are functional without minimal promoters. Applied to broadly expressed genes from human and mouse tissues, LSD generates functional housekeeper-like sLCRs compatible with size constraints of AAV vectors for gene therapy applications. A mesenchymal glioblastoma reporter designed by LSD outperforms previously validated ones and canonical cell surface markers. In genome-scale CRISPRa screens, LSD facilitates the discovery of known and novel bona fide cell-state drivers. Thus, LSD captures core principles of cis-regulation and is broadly applicable to studying complex cell states and mechanisms of transcriptional regulation., (© 2024. The Author(s).)
- Published
- 2024
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34. A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2.
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Losa M, Barozzi I, Osterwalder M, Hermosilla-Aguayo V, Morabito A, Chacón BH, Zarrineh P, Girdziusaite A, Benazet JD, Zhu J, Mackem S, Capellini TD, Dickel D, Bobola N, Zuniga A, Visel A, Zeller R, and Selleri L
- Subjects
- Animals, Mice, Homeodomain Proteins metabolism, Pre-B-Cell Leukemia Transcription Factor 1 genetics, Gene Regulatory Networks, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
A lingering question in developmental biology has centered on how transcription factors with widespread distribution in vertebrate embryos can perform tissue-specific functions. Here, using the murine hindlimb as a model, we investigate the elusive mechanisms whereby PBX TALE homeoproteins, viewed primarily as HOX cofactors, attain context-specific developmental roles despite ubiquitous presence in the embryo. We first demonstrate that mesenchymal-specific loss of PBX1/2 or the transcriptional regulator HAND2 generates similar limb phenotypes. By combining tissue-specific and temporally controlled mutagenesis with multi-omics approaches, we reconstruct a gene regulatory network (GRN) at organismal-level resolution that is collaboratively directed by PBX1/2 and HAND2 interactions in subsets of posterior hindlimb mesenchymal cells. Genome-wide profiling of PBX1 binding across multiple embryonic tissues further reveals that HAND2 interacts with subsets of PBX-bound regions to regulate limb-specific GRNs. Our research elucidates fundamental principles by which promiscuous transcription factors cooperate with cofactors that display domain-restricted localization to instruct tissue-specific developmental programs., (© 2023. The Author(s).)
- Published
- 2023
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35. MYC determines lineage commitment in KRAS-driven primary liver cancer development.
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D'Artista L, Moschopoulou AA, Barozzi I, Craig AJ, Seehawer M, Herrmann L, Minnich M, Kang TW, Rist E, Henning M, Klotz S, Heinzmann F, Harbig J, Sipos B, Longerich T, Eilers M, Dauch D, Zuber J, Wang XW, and Zender L
- Subjects
- Humans, Animals, Mice, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Transcription Factors metabolism, Bile Ducts, Intrahepatic pathology, Carcinoma, Hepatocellular pathology, Liver Neoplasms genetics, Liver Neoplasms metabolism, Cholangiocarcinoma genetics, Cholangiocarcinoma metabolism, Bile Duct Neoplasms pathology, Fatty Liver
- Abstract
Background & Aims: Primary liver cancer (PLC) comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), two frequent and lethal tumour types that differ regarding their tumour biology and responses to cancer therapies. Liver cells harbour a high degree of cellular plasticity and can give rise to either HCC or iCCA. However, little is known about the cell-intrinsic mechanisms directing an oncogenically transformed liver cell to either HCC or iCCA. The scope of this study was to identify cell-intrinsic factors determining lineage commitment in PLC., Methods: Cross-species transcriptomic and epigenetic profiling was applied to murine HCCs and iCCAs and to two human PLC cohorts. Integrative data analysis comprised epigenetic Landscape In Silico deletion Analysis (LISA) of transcriptomic data and Hypergeometric Optimization of Motif EnRichment (HOMER) analysis of chromatin accessibility data. Identified candidate genes were subjected to functional genetic testing in non-germline genetically engineered PLC mouse models (shRNAmir knockdown or overexpression of full-length cDNAs)., Results: Integrative bioinformatic analyses of transcriptomic and epigenetic data pinpointed the Forkhead-family transcription factors FOXA1 and FOXA2 as MYC-dependent determination factors of the HCC lineage. Conversely, the ETS family transcription factor ETS1 was identified as a determinant of the iCCA lineage, which was found to be suppressed by MYC during HCC development. Strikingly, shRNA-mediated suppression of FOXA1 and FOXA2 with concomitant ETS1 expression fully switched HCC to iCCA development in PLC mouse models., Conclusions: The herein reported data establish MYC as a key determinant of lineage commitment in PLC and provide a molecular explanation why common liver-damaging risk factors such as alcoholic or non-alcoholic steatohepatitis can lead to either HCC or iCCA., Impact and Implications: Liver cancer is a major health problem and comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), two frequent and lethal tumour types that differ regarding their morphology, tumour biology, and responses to cancer therapies. We identified the transcription factor and oncogenic master regulator MYC as a switch between HCC and iCCA development. When MYC levels are high at the time point when a hepatocyte becomes a tumour cell, an HCC is growing out. Conversely, if MYC levels are low at this time point, the result is the outgrowth of an iCCA. Our study provides a molecular explanation why common liver-damaging risk factors such as alcoholic or non-alcoholic steatohepatitis can lead to either HCC or iCCA. Furthermore, our data harbour potential for the development of better PLC therapies., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
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36. Cell Type- and Tissue-specific Enhancers in Craniofacial Development.
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Rajderkar SS, Paraiso K, Amaral ML, Kosicki M, Cook LE, Darbellay F, Spurrell CH, Osterwalder M, Zhu Y, Wu H, Afzal SY, Blow MJ, Kelman G, Barozzi I, Fukuda-Yuzawa Y, Akiyama JA, Afzal V, Tran S, Plajzer-Frick I, Novak CS, Kato M, Hunter RD, von Maydell K, Wang A, Lin L, Preissl S, Lisgo S, Ren B, Dickel DE, Pennacchio LA, and Visel A
- Abstract
The genetic basis of craniofacial birth defects and general variation in human facial shape remains poorly understood. Distant-acting transcriptional enhancers are a major category of non-coding genome function and have been shown to control the fine-tuned spatiotemporal expression of genes during critical stages of craniofacial development
1-3 . However, a lack of accurate maps of the genomic location and cell type-specific in vivo activities of all craniofacial enhancers prevents their systematic exploration in human genetics studies. Here, we combined histone modification and chromatin accessibility profiling from different stages of human craniofacial development with single-cell analyses of the developing mouse face to create a comprehensive catalogue of the regulatory landscape of facial development at tissue- and single cell-resolution. In total, we identified approximately 14,000 enhancers across seven developmental stages from weeks 4 through 8 of human embryonic face development. We used transgenic mouse reporter assays to determine the in vivo activity patterns of human face enhancers predicted from these data. Across 16 in vivo validated human enhancers, we observed a rich diversity of craniofacial subregions in which these enhancers are active in vivo . To annotate the cell type specificities of human-mouse conserved enhancers, we performed single-cell RNA-seq and single-nucleus ATAC-seq of mouse craniofacial tissues from embryonic days e11.5 to e15.5. By integrating these data across species, we find that the majority (56%) of human craniofacial enhancers are functionally conserved in mice, providing cell type- and embryonic stage-resolved predictions of their in vivo activity profiles. Using retrospective analysis of known craniofacial enhancers in combination with single cell-resolved transgenic reporter assays, we demonstrate the utility of these data for predicting the in vivo cell type specificity of enhancers. Taken together, our data provide an expansive resource for genetic and developmental studies of human craniofacial development., Competing Interests: Declaration of Interests Bing Ren is a co-founder of Arima Genomics, Inc, and Epigenome Technologies, Inc.- Published
- 2023
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37. Topologically associating domain boundaries are required for normal genome function.
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Rajderkar S, Barozzi I, Zhu Y, Hu R, Zhang Y, Li B, Alcaina Caro A, Fukuda-Yuzawa Y, Kelman G, Akeza A, Blow MJ, Pham Q, Harrington AN, Godoy J, Meky EM, von Maydell K, Hunter RD, Akiyama JA, Novak CS, Plajzer-Frick I, Afzal V, Tran S, Lopez-Rios J, Talkowski ME, Lloyd KCK, Ren B, Dickel DE, Visel A, and Pennacchio LA
- Subjects
- Animals, Mice, Phenotype, Chromatin genetics, Genome
- Abstract
Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes
1-3 , but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11-80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening., (© 2023. The Author(s).)- Published
- 2023
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38. The co-evolution of the genome and epigenome in colorectal cancer.
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Heide T, Househam J, Cresswell GD, Spiteri I, Lynn C, Mossner M, Kimberley C, Fernandez-Mateos J, Chen B, Zapata L, James C, Barozzi I, Chkhaidze K, Nichol D, Gunasri V, Berner A, Schmidt M, Lakatos E, Baker AM, Costa H, Mitchinson M, Piazza R, Jansen M, Caravagna G, Ramazzotti D, Shibata D, Bridgewater J, Rodriguez-Justo M, Magnani L, Graham TA, and Sottoriva A
- Subjects
- Humans, Adenoma genetics, Adenoma pathology, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Chromatin genetics, Chromatin metabolism, Oncogenes genetics, Transcription Factors metabolism, Interferons, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Epigenome genetics, Mutation, Genome, Human genetics
- Abstract
Colorectal malignancies are a leading cause of cancer-related death
1 and have undergone extensive genomic study2,3 . However, DNA mutations alone do not fully explain malignant transformation4-7 . Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology., (© 2022. The Author(s).)- Published
- 2022
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39. Genome-wide fetalization of enhancer architecture in heart disease.
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Spurrell CH, Barozzi I, Kosicki M, Mannion BJ, Blow MJ, Fukuda-Yuzawa Y, Slaven N, Afzal SY, Akiyama JA, Afzal V, Tran S, Plajzer-Frick I, Novak CS, Kato M, Lee EA, Garvin TH, Pham QT, Kronshage AN, Lisgo S, Bristow J, Cappola TP, Morley MP, Margulies KB, Pennacchio LA, Dickel DE, and Visel A
- Subjects
- Adult, Epigenome, Epigenomics, Humans, Transcription Factors, Cardiomyopathy, Dilated, Enhancer Elements, Genetic genetics
- Abstract
Heart disease is associated with re-expression of key transcription factors normally active only during prenatal development of the heart. However, the impact of this reactivation on the regulatory landscape in heart disease is unclear. Here, we use RNA-seq and ChIP-seq targeting a histone modification associated with active transcriptional enhancers to generate genome-wide enhancer maps from left ventricle tissue from up to 26 healthy controls, 18 individuals with idiopathic dilated cardiomyopathy (DCM), and five fetal hearts. Healthy individuals have a highly reproducible epigenomic landscape, consisting of more than 33,000 predicted heart enhancers. In contrast, we observe reproducible disease-associated changes in activity at 6,850 predicted heart enhancers. Combined analysis of adult and fetal samples reveals that the heart disease epigenome and transcriptome both acquire fetal-like characteristics, with 3,400 individual enhancers sharing fetal regulatory properties. We also provide a comprehensive data resource (http://heart.lbl.gov) for the mechanistic exploration of DCM etiology., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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40. Interferons reshape the 3D conformation and accessibility of macrophage chromatin.
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Platanitis E, Gruener S, Ravi Sundar Jose Geetha A, Boccuni L, Vogt A, Novatchkova M, Sommer A, Barozzi I, Müller M, and Decker T
- Abstract
Engagement of macrophages in innate immune responses is directed by type I and type II interferons (IFN-I and IFN-γ, respectively). IFN triggers drastic changes in cellular transcriptomes, executed by JAK-STAT signal transduction and the transcriptional control of interferon-stimulated genes (ISG) by STAT transcription factors. Here, we study the immediate-early nuclear response to IFN-I and IFN-γ in murine macrophages. We show that the mechanism of gene control by both cytokines includes a rapid increase of DNA accessibility and rearrangement of the 3D chromatin contacts particularly between open chromatin of ISG loci. IFN-stimulated gene factor 3 (ISGF3), the major transcriptional regulator of ISG, controlled homeostatic and, most notably, induced-state DNA accessibility at a subset of ISG. Increases in DNA accessibility correlated with the appearance of activating histone marks at surrounding nucleosomes. Collectively our data emphasize changes in the three-dimensional nuclear space and epigenome as an important facet of transcriptional control by the IFN-induced JAK-STAT pathway., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)
- Published
- 2022
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41. Transcriptional network orchestrating regional patterning of cortical progenitors.
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Ypsilanti AR, Pattabiraman K, Catta-Preta R, Golonzhka O, Lindtner S, Tang K, Jones IR, Abnousi A, Juric I, Hu M, Shen Y, Dickel DE, Visel A, Pennachio LA, Hawrylycz M, Thompson CL, Zeng H, Barozzi I, Nord AS, and Rubenstein JL
- Subjects
- Animals, COUP Transcription Factor I metabolism, Cerebral Cortex metabolism, Epigenome, Homeodomain Proteins metabolism, LIM-Homeodomain Proteins metabolism, Mice, PAX6 Transcription Factor metabolism, Pre-B-Cell Leukemia Transcription Factor 1 metabolism, Transcription Factors genetics, Cerebral Cortex embryology, Gene Regulatory Networks, Regulatory Elements, Transcriptional, Transcription Factors metabolism
- Abstract
We uncovered a transcription factor (TF) network that regulates cortical regional patterning in radial glial stem cells. Screening the expression of hundreds of TFs in the developing mouse cortex identified 38 TFs that are expressed in gradients in the ventricular zone (VZ). We tested whether their cortical expression was altered in mutant mice with known patterning defects ( Emx2, Nr2f1 , and Pax6 ), which enabled us to define a cortical regionalization TF network (CRTFN). To identify genomic programming underlying this network, we performed TF ChIP-seq and chromatin-looping conformation to identify enhancer-gene interactions. To map enhancers involved in regional patterning of cortical progenitors, we performed assays for epigenomic marks and DNA accessibility in VZ cells purified from wild-type and patterning mutant mice. This integrated approach has identified a CRTFN and VZ enhancers involved in cortical regional patterning in the mouse., Competing Interests: Competing interest statement: J.L.R. is a cofounder, stockholder, and currently on the scientific board of Neurona, a company studying the potential therapeutic use of interneuron transplantation., (Copyright © 2021 the Author(s). Published by PNAS.)
- Published
- 2021
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42. SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning.
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Gamart J, Barozzi I, Laurent F, Reinhardt R, Martins LR, Oberholzer T, Visel A, Zeller R, and Zuniga A
- Subjects
- Animals, Bone Morphogenetic Proteins genetics, Gene Expression Regulation, Developmental, Hedgehog Proteins genetics, Hindlimb embryology, Mice, Mice, Transgenic, Smad4 Protein genetics, Body Patterning, Bone Morphogenetic Proteins metabolism, Hedgehog Proteins metabolism, Limb Buds embryology, Signal Transduction, Smad4 Protein metabolism
- Abstract
SMAD4 regulates gene expression in response to BMP and TGFβ signal transduction, and is required for diverse morphogenetic processes, but its target genes have remained largely elusive. Here, we identify the SMAD4 target genes in mouse limb buds using an epitope-tagged Smad4 allele for ChIP-seq analysis in combination with transcription profiling. This analysis shows that SMAD4 predominantly mediates BMP signal transduction during early limb bud development. Unexpectedly, the expression of cholesterol biosynthesis enzymes is precociously downregulated and intracellular cholesterol levels are reduced in Smad4-deficient limb bud mesenchymal progenitors. Most importantly, our analysis reveals a predominant function of SMAD4 in upregulating target genes in the anterior limb bud mesenchyme. Analysis of differentially expressed genes shared between Smad4- and Shh-deficient limb buds corroborates this function of SMAD4 and also reveals the repressive effect of SMAD4 on posterior genes that are upregulated in response to SHH signaling. This analysis uncovers opposing trans-regulatory inputs from SHH- and SMAD4-mediated BMP signal transduction on anterior and posterior gene expression during the digit patterning and outgrowth in early limb buds., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)
- Published
- 2021
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43. A first exon termination checkpoint preferentially suppresses extragenic transcription.
- Author
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Austenaa LMI, Piccolo V, Russo M, Prosperini E, Polletti S, Polizzese D, Ghisletti S, Barozzi I, Diaferia GR, and Natoli G
- Subjects
- Alternative Splicing genetics, Animals, Chromosomal Proteins, Non-Histone ultrastructure, DNA-Binding Proteins ultrastructure, Exons genetics, Humans, Mice, Promoter Regions, Genetic genetics, RNA Polymerase II genetics, RNA Splicing genetics, RNA, Antisense genetics, RNA, Antisense ultrastructure, RNA, Long Noncoding ultrastructure, RNA, Messenger genetics, Regulatory Sequences, Nucleic Acid genetics, Chromosomal Proteins, Non-Histone genetics, DNA-Binding Proteins genetics, RNA Polymerase II ultrastructure, RNA, Long Noncoding genetics, Transcription, Genetic
- Abstract
Interactions between the splicing machinery and RNA polymerase II increase protein-coding gene transcription. Similarly, exons and splicing signals of enhancer-generated long noncoding RNAs (elncRNAs) augment enhancer activity. However, elncRNAs are inefficiently spliced, suggesting that, compared with protein-coding genes, they contain qualitatively different exons with a limited ability to drive splicing. We show here that the inefficiently spliced first exons of elncRNAs as well as promoter-antisense long noncoding RNAs (pa-lncRNAs) in human and mouse cells trigger a transcription termination checkpoint that requires WDR82, an RNA polymerase II-binding protein, and its RNA-binding partner of previously unknown function, ZC3H4. We propose that the first exons of elncRNAs and pa-lncRNAs are an intrinsic component of a regulatory mechanism that, on the one hand, maximizes the activity of these cis-regulatory elements by recruiting the splicing machinery and, on the other, contains elements that suppress pervasive extragenic transcription.
- Published
- 2021
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44. Long non-coding RNA TINCR suppresses metastatic melanoma dissemination by preventing ATF4 translation.
- Author
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Melixetian M, Bossi D, Mihailovich M, Punzi S, Barozzi I, Marocchi F, Cuomo A, Bonaldi T, Testa G, Marine JC, Leucci E, Minucci S, Pelicci PG, and Lanfrancone L
- Subjects
- Activating Transcription Factor 4 genetics, Activating Transcription Factor 4 metabolism, Cell Line, Tumor, Humans, Phosphorylation, RNA, Messenger metabolism, Melanoma genetics, Pharmaceutical Preparations, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism
- Abstract
Transition from proliferative-to-invasive phenotypes promotes metastasis and therapy resistance in melanoma. Reversion of the invasive phenotype, however, is challenged by the poor understanding of mechanisms underlying its maintenance. Here, we report that the lncRNA TINCR is down-regulated in metastatic melanoma and its silencing increases the expression levels of invasive markers, in vitro migration, in vivo tumor growth, and resistance to BRAF and MEK inhibitors. The critical mediator is ATF4, a central player of the integrated stress response (ISR), which is activated in TINCR-depleted cells in the absence of starvation and eIF2α phosphorylation. TINCR depletion increases global protein synthesis and induces translational reprogramming, leading to increased translation of mRNAs encoding ATF4 and other ISR proteins. Strikingly, re-expression of TINCR in metastatic melanoma suppresses the invasive phenotype, reduces numbers of tumor-initiating cells and metastasis formation, and increases drug sensitivity. Mechanistically, TINCR interacts with mRNAs associated with the invasive phenotype, including ATF4, preventing their binding to ribosomes. Thus, TINCR is a suppressor of the melanoma invasive phenotype, which functions in nutrient-rich conditions by repressing translation of selected ISR RNAs., (© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
- Published
- 2021
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45. Phenotypic Mapping of Pathologic Cross-Talk between Glioblastoma and Innate Immune Cells by Synthetic Genetic Tracing.
- Author
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Schmitt MJ, Company C, Dramaretska Y, Barozzi I, Göhrig A, Kertalli S, Großmann M, Naumann H, Sanchez-Bailon MP, Hulsman D, Glass R, Squatrito M, Serresi M, and Gargiulo G
- Subjects
- Biomarkers, Tumor, Disease Susceptibility, Glioblastoma metabolism, Humans, Neoplasm Grading, Neoplasm Staging, Transcriptome, Tumor Microenvironment, Cell Communication genetics, Gene Expression Regulation, Neoplastic, Glioblastoma etiology, Glioblastoma pathology, Immunity, Innate genetics
- Abstract
Glioblastoma is a lethal brain tumor that exhibits heterogeneity and resistance to therapy. Our understanding of tumor homeostasis is limited by a lack of genetic tools to selectively identify tumor states and fate transitions. Here, we use glioblastoma subtype signatures to construct synthetic genetic tracing cassettes and investigate tumor heterogeneity at cellular and molecular levels, in vitro and in vivo . Through synthetic locus control regions, we demonstrate that proneural glioblastoma is a hardwired identity, whereas mesenchymal glioblastoma is an adaptive and metastable cell state driven by proinflammatory and differentiation cues and DNA damage, but not hypoxia. Importantly, we discovered that innate immune cells divert glioblastoma cells to a proneural-to-mesenchymal transition that confers therapeutic resistance. Our synthetic genetic tracing methodology is simple, scalable, and widely applicable to study homeostasis in development and diseases. In glioblastoma, the method causally links distinct (micro)environmental, genetic, and pharmacologic perturbations and mesenchymal commitment. SIGNIFICANCE: Glioblastoma is heterogeneous and incurable. Here, we designed synthetic reporters to reflect the transcriptional output of tumor cell states and signaling pathways' activity. This method is generally applicable to study homeostasis in normal tissues and diseases. In glioblastoma, synthetic genetic tracing causally connects cellular and molecular heterogeneity to therapeutic responses. This article is highlighted in the In This Issue feature, p. 521 ., (©2020 American Association for Cancer Research.)
- Published
- 2021
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46. Author Correction: An atlas of dynamic chromatin landscapes in mouse fetal development.
- Author
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Gorkin DU, Barozzi I, Zhao Y, Zhang Y, Huang H, Lee AY, Li B, Chiou J, Wildberg A, Ding B, Zhang B, Wang M, Strattan JS, Davidson JM, Qiu Y, Afzal V, Akiyama JA, Plajzer-Frick I, Novak CS, Kato M, Garvin TH, Pham QT, Harrington AN, Mannion BJ, Lee EA, Fukuda-Yuzawa Y, He Y, Preissl S, Chee S, Han JY, Williams BA, Trout D, Amrhein H, Yang H, Cherry JM, Wang W, Gaulton K, Ecker JR, Shen Y, Dickel DE, Visel A, Pennacchio LA, and Ren B
- Published
- 2021
- Full Text
- View/download PDF
47. Evolution of Advanced Chronic Lymphoid Leukemia Unveiled by Single-Cell Transcriptomics: A Case Report.
- Author
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Ostasov P, Robertson H, Piazza P, Datta A, Apperley J, Houdova L, Lysak D, Holubova M, Tesarova K, Caputo VS, and Barozzi I
- Abstract
Genetic and transcriptional heterogeneity of Chronic lymphocytic leukaemia (CLL) limits prevention of disease progression. Longitudinal single-cell transcriptomics represents the state-of-the-art method to profile the disease heterogeneity at diagnosis and to inform about disease evolution. Here, we apply single-cell RNA-seq to a CLL case, sampled at diagnosis and relapse, that was treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) and underwent a dramatic decrease in CD19 expression during disease progression. Computational analyses revealed a major switch in clones' dominance during treatment. The clone that expanded at relapse showed 17p and 3p chromosomal deletions, and up-regulation of pathways related to motility, cytokine signaling and antigen presentation. Single-cell RNA-seq uniquely revealed that this clone was already present at low frequency at diagnosis, and it displays feature of plasma cell differentiation, consistent with a more aggressive phenotype. This study shows the benefit of single-cell profiling of CLL heterogeneity at diagnosis, to identify clones that might otherwise not be recognized and to determine the best treatment options., (Copyright © 2020 Ostasov, Robertson, Piazza, Datta, Apperley, Houdova, Lysak, Holubova, Tesarova, Caputo and Barozzi.)
- Published
- 2020
- Full Text
- View/download PDF
48. Author Correction: An atlas of dynamic chromatin landscapes in mouse fetal development.
- Author
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Gorkin DU, Barozzi I, Zhao Y, Zhang Y, Huang H, Lee AY, Li B, Chiou J, Wildberg A, Ding B, Zhang B, Wang M, Strattan JS, Davidson JM, Qiu Y, Afzal V, Akiyama JA, Plajzer-Frick I, Novak CS, Kato M, Garvin TH, Pham QT, Harrington AN, Mannion BJ, Lee EA, Fukuda-Yuzawa Y, He Y, Preissl S, Chee S, Han JY, Williams BA, Trout D, Amrhein H, Yang H, Cherry JM, Wang W, Gaulton K, Ecker JR, Shen Y, Dickel DE, Visel A, Pennacchio LA, and Ren B
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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49. Supervised enhancer prediction with epigenetic pattern recognition and targeted validation.
- Author
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Sethi A, Gu M, Gumusgoz E, Chan L, Yan KK, Rozowsky J, Barozzi I, Afzal V, Akiyama JA, Plajzer-Frick I, Yan C, Novak CS, Kato M, Garvin TH, Pham Q, Harrington A, Mannion BJ, Lee EA, Fukuda-Yuzawa Y, Visel A, Dickel DE, Yip KY, Sutton R, Pennacchio LA, and Gerstein M
- Subjects
- Animals, Cell Line, Drosophila, Histones genetics, Histones metabolism, Humans, Mice, Mice, Transgenic, Reproducibility of Results, Epigenesis, Genetic physiology, Pattern Recognition, Automated methods
- Abstract
Enhancers are important non-coding elements, but they have traditionally been hard to characterize experimentally. The development of massively parallel assays allows the characterization of large numbers of enhancers for the first time. Here, we developed a framework using Drosophila STARR-seq to create shape-matching filters based on meta-profiles of epigenetic features. We integrated these features with supervised machine-learning algorithms to predict enhancers. We further demonstrated that our model could be transferred to predict enhancers in mammals. We comprehensively validated the predictions using a combination of in vivo and in vitro approaches, involving transgenic assays in mice and transduction-based reporter assays in human cell lines (153 enhancers in total). The results confirmed that our model can accurately predict enhancers in different species without re-parameterization. Finally, we examined the transcription factor binding patterns at predicted enhancers versus promoters. We demonstrated that these patterns enable the construction of a secondary model that effectively distinguishes enhancers and promoters.
- Published
- 2020
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50. An atlas of dynamic chromatin landscapes in mouse fetal development.
- Author
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Gorkin DU, Barozzi I, Zhao Y, Zhang Y, Huang H, Lee AY, Li B, Chiou J, Wildberg A, Ding B, Zhang B, Wang M, Strattan JS, Davidson JM, Qiu Y, Afzal V, Akiyama JA, Plajzer-Frick I, Novak CS, Kato M, Garvin TH, Pham QT, Harrington AN, Mannion BJ, Lee EA, Fukuda-Yuzawa Y, He Y, Preissl S, Chee S, Han JY, Williams BA, Trout D, Amrhein H, Yang H, Cherry JM, Wang W, Gaulton K, Ecker JR, Shen Y, Dickel DE, Visel A, Pennacchio LA, and Ren B
- Subjects
- Animals, Chromatin chemistry, Chromatin Immunoprecipitation Sequencing, Disease genetics, Enhancer Elements, Genetic genetics, Female, Gene Expression Regulation, Developmental genetics, Genetic Variation, Histones chemistry, Humans, Male, Mice, Mice, Inbred C57BL, Organ Specificity genetics, Reproducibility of Results, Transposases metabolism, Chromatin genetics, Chromatin metabolism, Datasets as Topic, Fetal Development genetics, Histones metabolism, Molecular Sequence Annotation, Regulatory Sequences, Nucleic Acid genetics
- Abstract
The Encyclopedia of DNA Elements (ENCODE) project has established a genomic resource for mammalian development, profiling a diverse panel of mouse tissues at 8 developmental stages from 10.5 days after conception until birth, including transcriptomes, methylomes and chromatin states. Here we systematically examined the state and accessibility of chromatin in the developing mouse fetus. In total we performed 1,128 chromatin immunoprecipitation with sequencing (ChIP-seq) assays for histone modifications and 132 assay for transposase-accessible chromatin using sequencing (ATAC-seq) assays for chromatin accessibility across 72 distinct tissue-stages. We used integrative analysis to develop a unified set of chromatin state annotations, infer the identities of dynamic enhancers and key transcriptional regulators, and characterize the relationship between chromatin state and accessibility during developmental gene regulation. We also leveraged these data to link enhancers to putative target genes and demonstrate tissue-specific enrichments of sequence variants associated with disease in humans. The mouse ENCODE data sets provide a compendium of resources for biomedical researchers and achieve, to our knowledge, the most comprehensive view of chromatin dynamics during mammalian fetal development to date.
- Published
- 2020
- Full Text
- View/download PDF
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