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1. The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models.

Author

Rozowsky, Joel, Gao, Jiahao, Borsari, Beatrice, Yang, Yucheng, Galeev, Timur, Gürsoy, Gamze, Epstein, Charles, Xiong, Kun, Xu, Jinrui, Li, Tianxiao, Liu, Jason, Yu, Keyang, Berthel, Ana, Chen, Zhanlin, Navarro, Fabio, Sun, Maxwell, Wright, James, Chang, Justin, Cameron, Christopher, Shoresh, Noam, Gaskell, Elizabeth, Drenkow, Jorg, Adrian, Jessika, Aganezov, Sergey, Aguet, François, Balderrama-Gutierrez, Gabriela, Banskota, Samridhi, Corona, Guillermo, Chee, Sora, Chhetri, Surya, Cortez Martins, Gabriel, Danyko, Cassidy, Davis, Carrie, Farid, Daniel, Farrell, Nina, Gabdank, Idan, Gofin, Yoel, Gorkin, David, Gu, Mengting, Hecht, Vivian, Hitz, Benjamin, Issner, Robbyn, Jiang, Yunzhe, Kirsche, Melanie, Kong, Xiangmeng, Lam, Bonita, Li, Shantao, Li, Bian, Li, Xiqi, Lin, Khine, Luo, Ruibang, Mackiewicz, Mark, Meng, Ran, Moore, Jill, Mudge, Jonathan, Nelson, Nicholas, Nusbaum, Chad, Popov, Ioann, Pratt, Henry, Qiu, Yunjiang, Ramakrishnan, Srividya, Raymond, Joe, Salichos, Leonidas, Scavelli, Alexandra, Schreiber, Jacob, Sedlazeck, Fritz, See, Lei, Sherman, Rachel, Shi, Xu, Shi, Minyi, Sloan, Cricket, Strattan, J, Tan, Zhen, Tanaka, Forrest, Vlasova, Anna, Wang, Jun, Werner, Jonathan, Williams, Brian, Xu, Min, Yan, Chengfei, Yu, Lu, Zaleski, Christopher, Zhang, Jing, Ardlie, Kristin, Cherry, J, Mendenhall, Eric, Noble, William, Weng, Zhiping, Levine, Morgan, Dobin, Alexander, Wold, Barbara, Mortazavi, Ali, Ren, Bing, Gillis, Jesse, Myers, Richard, Choudhary, Jyoti, Milosavljevic, Aleksandar, Schatz, Michael, Bernstein, Bradley, and Guigó, Roderic

Subjects
ENCODE, GTEx, allele-specific activity, eQTLs, functional epigenomes, functional genomics, genome annotations, personal genome, predictive models, structural variants, tissue specificity, transformer model, Epigenome, Quantitative Trait Loci, Genome-Wide Association Study, Genomics, Phenotype, Polymorphism, Single Nucleotide
Abstract

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

Published
2023

2. Author Correction: Expanded encyclopaedias of DNA elements in the human and mouse genomes

Author

Moore, Jill E, Purcaro, Michael J, Pratt, Henry E, Epstein, Charles B, Shoresh, Noam, Adrian, Jessika, Kawli, Trupti, Davis, Carrie A, Dobin, Alexander, Kaul, Rajinder, Halow, Jessica, Van Nostrand, Eric L, Freese, Peter, Gorkin, David U, Shen, Yin, He, Yupeng, Mackiewicz, Mark, Pauli-Behn, Florencia, Williams, Brian A, Mortazavi, Ali, Keller, Cheryl A, Zhang, Xiao-Ou, Elhajjajy, Shaimae I, Huey, Jack, Dickel, Diane E, Snetkova, Valentina, Wei, Xintao, Wang, Xiaofeng, Rivera-Mulia, Juan Carlos, Rozowsky, Joel, Zhang, Jing, Chhetri, Surya B, Zhang, Jialing, Victorsen, Alec, White, Kevin P, Visel, Axel, Yeo, Gene W, Burge, Christopher B, Lécuyer, Eric, Gilbert, David M, Dekker, Job, Rinn, John, Mendenhall, Eric M, Ecker, Joseph R, Kellis, Manolis, Klein, Robert J, Noble, William S, Kundaje, Anshul, Guigó, Roderic, Farnham, Peggy J, Cherry, J Michael, Myers, Richard M, Ren, Bing, Graveley, Brenton R, Gerstein, Mark B, Pennacchio, Len A, Snyder, Michael P, Bernstein, Bradley E, Wold, Barbara, Hardison, Ross C, Gingeras, Thomas R, Stamatoyannopoulos, John A, and Weng, Zhiping

Subjects
ENCODE Project Consortium, General Science & Technology
Abstract

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.

Published
2022

4. Expanded encyclopaedias of DNA elements in the human and mouse genomes

Author

Moore, Jill E, Purcaro, Michael J, Pratt, Henry E, Epstein, Charles B, Shoresh, Noam, Adrian, Jessika, Kawli, Trupti, Davis, Carrie A, Dobin, Alexander, Kaul, Rajinder, Halow, Jessica, Van Nostrand, Eric L, Freese, Peter, Gorkin, David U, Shen, Yin, He, Yupeng, Mackiewicz, Mark, Pauli-Behn, Florencia, Williams, Brian A, Mortazavi, Ali, Keller, Cheryl A, Zhang, Xiao-Ou, Elhajjajy, Shaimae I, Huey, Jack, Dickel, Diane E, Snetkova, Valentina, Wei, Xintao, Wang, Xiaofeng, Rivera-Mulia, Juan Carlos, Rozowsky, Joel, Zhang, Jing, Chhetri, Surya B, Zhang, Jialing, Victorsen, Alec, White, Kevin P, Visel, Axel, Yeo, Gene W, Burge, Christopher B, Lécuyer, Eric, Gilbert, David M, Dekker, Job, Rinn, John, Mendenhall, Eric M, Ecker, Joseph R, Kellis, Manolis, Klein, Robert J, Noble, William S, Kundaje, Anshul, Guigó, Roderic, Farnham, Peggy J, Cherry, J Michael, Myers, Richard M, Ren, Bing, Graveley, Brenton R, Gerstein, Mark B, Pennacchio, Len A, Snyder, Michael P, Bernstein, Bradley E, Wold, Barbara, Hardison, Ross C, Gingeras, Thomas R, Stamatoyannopoulos, John A, and Weng, Zhiping

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, 1.1 Normal biological development and functioning, Animals, Chromatin, DNA, DNA Footprinting, DNA Methylation, DNA Replication Timing, Databases, Genetic, Deoxyribonuclease I, Genome, Genome, Human, Genomics, Histones, Humans, Mice, Mice, Transgenic, Molecular Sequence Annotation, RNA-Binding Proteins, Registries, Regulatory Sequences, Nucleic Acid, Transcription, Genetic, Transposases, ENCODE Project Consortium, General Science & Technology
Abstract

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.

Published
2020

5. Expanded encyclopaedias of DNA elements in the human and mouse genomes.

Author

ENCODE Project Consortium, Moore, Jill E, Purcaro, Michael J, Pratt, Henry E, Epstein, Charles B, Shoresh, Noam, Adrian, Jessika, Kawli, Trupti, Davis, Carrie A, Dobin, Alexander, Kaul, Rajinder, Halow, Jessica, Van Nostrand, Eric L, Freese, Peter, Gorkin, David U, Shen, Yin, He, Yupeng, Mackiewicz, Mark, Pauli-Behn, Florencia, Williams, Brian A, Mortazavi, Ali, Keller, Cheryl A, Zhang, Xiao-Ou, Elhajjajy, Shaimae I, Huey, Jack, Dickel, Diane E, Snetkova, Valentina, Wei, Xintao, Wang, Xiaofeng, Rivera-Mulia, Juan Carlos, Rozowsky, Joel, Zhang, Jing, Chhetri, Surya B, Zhang, Jialing, Victorsen, Alec, White, Kevin P, Visel, Axel, Yeo, Gene W, Burge, Christopher B, Lécuyer, Eric, Gilbert, David M, Dekker, Job, Rinn, John, Mendenhall, Eric M, Ecker, Joseph R, Kellis, Manolis, Klein, Robert J, Noble, William S, Kundaje, Anshul, Guigó, Roderic, Farnham, Peggy J, Cherry, J Michael, Myers, Richard M, Ren, Bing, Graveley, Brenton R, Gerstein, Mark B, Pennacchio, Len A, Snyder, Michael P, Bernstein, Bradley E, Wold, Barbara, Hardison, Ross C, Gingeras, Thomas R, Stamatoyannopoulos, John A, and Weng, Zhiping

Subjects
ENCODE Project Consortium, Chromatin, Animals, Mice, Transgenic, Humans, Mice, Deoxyribonuclease I, Transposases, RNA-Binding Proteins, Histones, DNA, Registries, DNA Footprinting, Genomics, DNA Methylation, DNA Replication Timing, Transcription, Genetic, Regulatory Sequences, Nucleic Acid, Genome, Genome, Human, Databases, Genetic, Molecular Sequence Annotation, Human Genome, HIV/AIDS, Vaccine Related, Biotechnology, Genetics, Immunization, Vaccine Related (AIDS), Prevention, 1.1 Normal biological development and functioning, Generic health relevance, General Science & Technology
Abstract

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.

Published
2020

6. “Multiplexed screen identifies aPseudomonas aeruginosa-specific small molecule targeting the outer membrane protein OprH and its interaction with LPS”

Author

Poulsen, Bradley E., primary, Warrier, Thulasi, additional, Barkho, Sulyman, additional, Bagnall, Josephine, additional, Romano, Keith P., additional, White, Tiantian, additional, Yu, Xiao, additional, Kawate, Tomohiko, additional, Nguyen, Phuong H., additional, Raines, Kyra, additional, Ferrara, Kristina, additional, Golas, Aaron, additional, Fitzgerald, Michael, additional, Boeszoermenyi, Andras, additional, Kaushik, Virendar, additional, Serrano-Wu, Michael, additional, Shoresh, Noam, additional, and Hung, Deborah T., additional

Published
2024
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9. Genetic and epigenetic fine mapping of causal autoimmune disease variants

Author

Farh, Kyle Kai-How, Marson, Alexander, Zhu, Jiang, Kleinewietfeld, Markus, Housley, William J, Beik, Samantha, Shoresh, Noam, Whitton, Holly, Ryan, Russell JH, Shishkin, Alexander A, Hatan, Meital, Carrasco-Alfonso, Marlene J, Mayer, Dita, Luckey, C John, Patsopoulos, Nikolaos A, De Jager, Philip L, Kuchroo, Vijay K, Epstein, Charles B, Daly, Mark J, Hafler, David A, and Bernstein, Bradley E

Subjects
Immunization, Human Genome, Vaccine Related, Autoimmune Disease, Genetics, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, Inflammatory and immune system, Autoimmune Diseases, Base Sequence, Chromatin, Consensus Sequence, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Genome-Wide Association Study, Humans, Nucleotide Motifs, Organ Specificity, Polymorphism, Single Nucleotide, T-Lymphocytes, Transcription Factors, General Science & Technology
Abstract

Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that ∼90% of causal variants are non-coding, with ∼60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

Published
2015

10. Simultaneous detection of genotype and phenotype enables rapid and accurate antibiotic susceptibility determination

Author

Bhattacharyya, Roby P., Bandyopadhyay, Nirmalya, Ma, Peijun, Son, Sophie S., Liu, Jamin, He, Lorrie L., Wu, Lidan, Khafizov, Rustem, Boykin, Rich, Cerqueira, Gustavo C., Pironti, Alejandro, Rudy, Robert F., Patel, Milesh M., Yang, Rui, Skerry, Jennifer, Nazarian, Elizabeth, Musser, Kimberly A., Taylor, Jill, Pierce, Virginia M., Earl, Ashlee M., Cosimi, Lisa A., Shoresh, Noam, Beechem, Joseph, Livny, Jonathan, and Hung, Deborah T.

Published
2019
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11. Comparative analysis of metazoan chromatin organization

Author

Ho, Joshua WK, Jung, Youngsook L, Liu, Tao, Alver, Burak H, Lee, Soohyun, Ikegami, Kohta, Sohn, Kyung-Ah, Minoda, Aki, Tolstorukov, Michael Y, Appert, Alex, Parker, Stephen CJ, Gu, Tingting, Kundaje, Anshul, Riddle, Nicole C, Bishop, Eric, Egelhofer, Thea A, Hu, Sheng'en Shawn, Alekseyenko, Artyom A, Rechtsteiner, Andreas, Asker, Dalal, Belsky, Jason A, Bowman, Sarah K, Chen, Q Brent, Chen, Ron A-J, Day, Daniel S, Dong, Yan, Dose, Andrea C, Duan, Xikun, Epstein, Charles B, Ercan, Sevinc, Feingold, Elise A, Ferrari, Francesco, Garrigues, Jacob M, Gehlenborg, Nils, Good, Peter J, Haseley, Psalm, He, Daniel, Herrmann, Moritz, Hoffman, Michael M, Jeffers, Tess E, Kharchenko, Peter V, Kolasinska-Zwierz, Paulina, Kotwaliwale, Chitra V, Kumar, Nischay, Langley, Sasha A, Larschan, Erica N, Latorre, Isabel, Libbrecht, Maxwell W, Lin, Xueqiu, Park, Richard, Pazin, Michael J, Pham, Hoang N, Plachetka, Annette, Qin, Bo, Schwartz, Yuri B, Shoresh, Noam, Stempor, Przemyslaw, Vielle, Anne, Wang, Chengyang, Whittle, Christina M, Xue, Huiling, Kingston, Robert E, Kim, Ju Han, Bernstein, Bradley E, Dernburg, Abby F, Pirrotta, Vincenzo, Kuroda, Mitzi I, Noble, William S, Tullius, Thomas D, Kellis, Manolis, MacAlpine, David M, Strome, Susan, Elgin, Sarah CR, Liu, Xiaole Shirley, Lieb, Jason D, Ahringer, Julie, Karpen, Gary H, and Park, Peter J

Subjects
Biochemistry and Cell Biology, Biological Sciences, Immunization, Human Genome, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Animals, Caenorhabditis elegans, Cell Line, Centromere, Chromatin, Chromatin Assembly and Disassembly, DNA Replication, Drosophila melanogaster, Enhancer Elements, Genetic, Epigenesis, Genetic, Heterochromatin, Histones, Humans, Molecular Sequence Annotation, Nuclear Lamina, Nucleosomes, Promoter Regions, Genetic, Species Specificity, General Science & Technology
Abstract

Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.

Published
2014

13. Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors

Author

Cejas, Paloma, Drier, Yotam, Dreijerink, Koen M. A., Brosens, Lodewijk A. A., Deshpande, Vikram, Epstein, Charles B., Conemans, Elfi B., Morsink, Folkert H. M., Graham, Mindy K., Valk, Gerlof D., Vriens, Menno R., Castillo, Carlos Fernandez-del, Ferrone, Cristina R., Adar, Tomer, Bowden, Michaela, Whitton, Holly J., Da Silva, Annacarolina, Font-Tello, Alba, Long, Henry W., Gaskell, Elizabeth, Shoresh, Noam, Heaphy, Christopher M., Sicinska, Ewa, Kulke, Matthew H., Chung, Daniel C., Bernstein, Bradley E., and Shivdasani, Ramesh A.

Published
2019
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15. Single-cell multi-scale footprinting reveals the modular organization of DNA regulatory elements

Author

Hu, Yan, primary, Ma, Sai, additional, Kartha, Vinay K., additional, Duarte, Fabiana M., additional, Horlbeck, Max, additional, Zhang, Ruochi, additional, Shrestha, Rojesh, additional, Labade, Ajay, additional, Kletzien, Heidi, additional, Meliki, Alia, additional, Castillo, Andrew, additional, Durand, Neva, additional, Mattei, Eugenio, additional, Anderson, Lauren J., additional, Tay, Tristan, additional, Earl, Andrew S., additional, Shoresh, Noam, additional, Epstein, Charles B., additional, Wagers, Amy, additional, and Buenrostro, Jason D., additional

Published
2023
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17. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types

Author

Finucane, Hilary K., Reshef, Yakir A., Anttila, Verneri, Slowikowski, Kamil, Gusev, Alexander, Byrnes, Andrea, Gazal, Steven, Loh, Po-Ru, Lareau, Caleb, Shoresh, Noam, Genovese, Giulio, Saunders, Arpiar, Macosko, Evan, Pollack, Samuela, Perry, John R. B., Buenrostro, Jason D., Bernstein, Bradley E., Raychaudhuri, Soumya, McCarroll, Steven, Neale, Benjamin M., and Price, Alkes L.

Published
2018
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20. Rapid identification and phylogenetic classification of diverse bacterial pathogens in a multiplexed hybridization assay targeting ribosomal RNA

Author

Bhattacharyya, Roby P., Walker, Mark, Boykin, Rich, Son, Sophie S., Liu, Jamin, Hachey, Austin C., Ma, Peijun, Wu, Lidan, Choi, Kyungyong, Cummins, Kaelyn C., Benson, Maura, Skerry, Jennifer, Ryu, Hyunryul, Wong, Sharon Y., Goldberg, Marcia B., Han, Jongyoon, Pierce, Virginia M., Cosimi, Lisa A., Shoresh, Noam, Livny, Jonathan, Beechem, Joseph, and Hung, Deborah T.

Published
2019
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21. At-home Testing and Risk Factors for Acquisition of SARS-CoV-2 Infection in a Major US Metropolitan Area

Author

Woolley, Ann E, primary, Dryden-Peterson, Scott, additional, Kim, Andy, additional, Naz-McLean, Sarah, additional, Kelly, Christina, additional, Laibinis, Hannah H, additional, Bagnall, Josephine, additional, Livny, Jonathan, additional, Ma, Peijun, additional, Orzechowski, Marek, additional, Gomez, James, additional, Shoresh, Noam, additional, Gabriel, Stacey, additional, Hung, Deborah T, additional, and Cosimi, Lisa A, additional

Published
2022
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22. Publisher Correction: Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors

Author

Cejas, Paloma, Drier, Yotam, Dreijerink, Koen M. A., Brosens, Lodewijk A. A., Deshpande, Vikram, Epstein, Charles B., Conemans, Elfi B., Morsink, Folkert H. M., Graham, Mindy K., Valk, Gerlof D., Vriens, Menno R., Castillo, Carlos Fernandez-del, Ferrone, Cristina R., Adar, Tomer, Bowden, Michaela, Whitton, Holly J., Da Silva, Annacarolina, Font-Tello, Alba, Long, Henry W., Gaskell, Elizabeth, Shoresh, Noam, Heaphy, Christopher M., Sicinska, Ewa, Kulke, Matthew H., Chung, Daniel C., Bernstein, Bradley E., and Shivdasani, Ramesh A.

Published
2019
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23. Author Correction: Expanded encyclopaedias of DNA elements in the human and mouse genomes

Author

ENCODE Project Consortium, Moore, Jill E, Purcaro, Michael J, Pratt, Henry E, Epstein, Charles B, Shoresh, Noam, Adrian, Jessika, Kawli, Trupti, Davis, Carrie A, Dobin, Alexander, Kaul, Rajinder, Halow, Jessica, Van Nostrand, Eric L, Freese, Peter, Gorkin, David U, Shen, Yin, He, Yupeng, Mackiewicz, Mark, Pauli-Behn, Florencia, Williams, Brian A, Mortazavi, Ali, Keller, Cheryl A, Zhang, Xiao-Ou, Elhajjajy, Shaimae I, Huey, Jack, Dickel, Diane E, Snetkova, Valentina, Wei, Xintao, Wang, Xiaofeng, Rivera-Mulia, Juan Carlos, Rozowsky, Joel, Zhang, Jing, Chhetri, Surya B, Zhang, Jialing, Victorsen, Alec, White, Kevin P, Visel, Axel, Yeo, Gene W, Burge, Christopher B, Lécuyer, Eric, Gilbert, David M, Dekker, Job, Rinn, John, Mendenhall, Eric M, Ecker, Joseph R, Kellis, Manolis, Klein, Robert J, Noble, William S, Kundaje, Anshul, Guigó, Roderic, Farnham, Peggy J, Cherry, J Michael, Myers, Richard M, Ren, Bing, Graveley, Brenton R, Gerstein, Mark B, Pennacchio, Len A, Snyder, Michael P, Bernstein, Bradley E, Wold, Barbara, Hardison, Ross C, Gingeras, Thomas R, Stamatoyannopoulos, John A, and Weng, Zhiping

Subjects
ENCODE Project Consortium, General Science & Technology
Abstract

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.

Published
2022

24. Polyploidy can drive rapid adaptation in yeast

Author

Selmecki, Anna M., Maruvka, Yosef E., Richmond, Phillip A., Guillet, Marie, Shoresh, Noam, Sorenson, Amber L., De, Subhajyoti, Kishony, Roy, Michor, Franziska, Dowell, Robin, and Pellman, David

Subjects
Yeast fungi -- Research, Biological research, Biology, Experimental, Adaptation (Biology) -- Research, Polyploidy -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Polyploidy is observed across the tree of life, yet its influence on evolution remains incompletely understood (1-4). Polyploidy, usually whole-genome duplication, is proposed to alter the rate of evolutionary adaptation. This could occur through complex effects on the frequency or fitness of beneficial mutations (2, 5-7). For example, in diverse cell types and organisms, immediately after a whole-genome duplication, newly formed polyploids missegregate chromosomes and undergo genetic instability (8-13). The instability following whole-genome duplications is thought to provide adaptive mutations in microorganisms (13, 14) and can promote tumorigenesis in mammalian cells (11, 15). Polyploidy may also affect adaptation independently of beneficial mutations through ploidy-specific changes in cell physiology (16). Here we perform in vitro evolution experiments to test directly whether polyploidy can accelerate evolutionary adaptation. Compared with haploids and diploids, tetraploids undergo significantly faster adaptation. Mathematical modelling suggests that rapid adaptation of tetraploids is driven by higher rates of beneficial mutations with stronger fitness effects, which is supported by whole-genome sequencing and phenotypic analyses of evolved clones. Chromosome aneuploidy, concerted chromosome loss, and point mutations all provide large fitness gains. We identify several mutations whose beneficial effects are manifest specifically in the tetraploid strains. Together, these results provide direct quantitative evidence that in some environments polyploidy can accelerate evolutionary adaptation., To determine how polyploidy affects the rate of adaptation, we performed hundreds of independent passaging experiments in a poor carbonsource medium (raffinose, Fig. 1a), comparing isogenic haploid (1N), diploid (2N), [...]

Published
2015

25. Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations

Author

Fridman, Ofer, Goldberg, Amir, Ronin, Irine, Shoresh, Noam, and Balaban, Nathalie Q.

Subjects
Drug resistance in microorganisms -- Natural history, Drug tolerance -- Natural history, Microbial colonies -- Natural history, Antibiotics -- Dosage and administration, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The great therapeutic achievements of antibiotics have been dramatically undercut by the evolution of bacterial strategies that overcome antibiotic stress (1,2). These strategies fall into two classes. 'Resistance' makes it possible for a microorganism to grow in the constant presence of the antibiotic, provided that the concentration of the antibiotic is not too high. 'Tolerance' allows a microorganism to survive antibiotic treatment, even at high antibiotic concentrations, as long as the duration of the treatment is limited. Although both resistance and tolerance are important reasons for the failure of antibiotic treatments (3-6), the evolution of resistance (7-9) is much better understood than that of tolerance. Here we followed the evolution of bacterial populations under intermittent exposure to the high concentrations of antibiotics used in the clinic and characterized the evolved strains in terms of both resistance and tolerance. We found that all strains adapted by specific genetic mutations, which became fixed in the evolved populations. By monitoring the phenotypic changes at the population and single-cell levels, we found that the first adaptive change to antibiotic stress was the development of tolerance through a major adjustment in the single-cell lag-time distribution, without a change in resistance. Strikingly, we found that the lag time of bacteria before regrowth was optimized to match the duration of the antibiotic-exposure interval. Whole genome sequencing of the evolved strains and restoration of the wild-type alleles allowed us to identify target genes involved in this antibiotic-driven phenotype: 'tolerance by lag' (tbl). Better understanding of lag-time evolution as a key determinant of the survival of bacterial populations under high antibiotic concentrations could lead to new approaches to impeding the evolution of antibiotic resistance., We exposed batch cultures of the bacterium Escherichia coli to a high concentration of ampicillin (100 µg [ml.sup.-1]), which is 15 times greater than the minimum inhibitory concentration (MIC), in [...]

Published
2014

26. At-home Testing and Risk Factors for Acquisition of SARS-CoV-2 Infection in a Major US Metropolitan Area

Author

Woolley, Ann E., primary, Dryden-Peterson, Scott, additional, Kim, Andy, additional, Naz-McLean, Sarah, additional, Kelly, Christina, additional, Laibinis, Hannah H., additional, Bagnall, Josephine, additional, Livny, Jonathan, additional, Ma, Peijun, additional, Orzechowski, Marek, additional, Shoresh, Noam, additional, Gabriel, Stacey, additional, Hung, Deborah T., additional, and Cosimi, Lisa A., additional

Published
2022
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28. Integrative analysis of 111 reference human epigenomes

Author

Consortium, Roadmap Epigenomics, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Heravi-Moussavi, Alireza, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ziller, Michael J., Whitaker, John W., Ward, Lucas D., Sarkar, Abhishek, Sandstrom, Richard S., Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Harris, Alan R., Epstein, Charles B., Leung, Danny, Hawkins, David R., Hong, Chibo, Mungall, Andrew J., Chuah, Eric, Hansen, Scott R., Bansal, Mukul S., Dixon, Jesse R., Feizi, Soheil, Kim, Ah-Ram, Li, Daofeng, Elliott, GiNell, Neph, Shane J., Polak, Paz, Ray, Pradipta, Siebenthall, Kyle T., Thurman, Robert E., Zhou, Xin, Boyer, Laurie A., De Jager, Philip L., Fisher, Susan J., Li, Wei, McManus, Michael T., Sunyaev, Shamil, Tlsty, Thea D., Wang, Wei, Waterland, Robert A., Costello, Joseph F., Hirst, Martin, Stamatoyannopoulos, John A., Wang, Ting, Amin, Viren, Schultz, Matthew D., Quon, Gerald, Eaton, Matthew L., Pfenning, Andreas, Liu, Melina ClaussnitzerYaping, Coarfa, Cristian, Shoresh, Noam, Gjoneska, Elizabeta, Xie, Wei, Lister, Ryan, Moore, Richard, Tam, Angela, Canfield, Theresa K., Kaul, Rajinder, Sabo, Peter J., Carles, Annaick, Farh, Kai-How, Karlic, Rosa, Kulkarni, Ashwinikumar, Lowdon, Rebecca, Mercer, Tim R., Onuchic, Vitor, Rajagopal, Nisha, Sallari, Richard C., Sinnott-Armstrong, Nicholas A., Stevens, Michael, Wu, Jie, Zhang, Bo, Abdennur, Nezar, Adli, Mazhar, Akerman, Martin, Barrera, Luis, Antosiewicz-Bourget, Jessica, Ballinger, Tracy, Barnes, Michael J., Bates, Daniel, Bell, Robert J. A., Bennett, David A., Bianco, Katherine, Bock, Christoph, Boyle, Patrick, Brinchmann, Jan, Caballero-Campo, Pedro, Camahort, Raymond, Carrasco-Alfonso, Marlene J., Charnecki, Timothy, Chen, Huaming, Chen, Zhao, Cheng, Jeffrey B., Cho, Stephanie, Chu, Andy, Chung, Wen-Yu, Cowan, Chad, Deng, Qixia Athena, Deshpande, Vikram, Diegel, Morgan, Ding, Bo, Durham, Timothy, Echipare, Lorigail, Edsall, Lee, Flowers, David, Genbacev-Krtolica, Olga, Gifford, Casey, Gillespie, Shawn, Giste, Erika, Glass, Ian A., Gnirke, Andreas, Gormley, Matthew, Gu, Hongcang, Gu, Junchen, Hafler, David A., Hangauer, Matthew J., Hariharan, Manoj, Hatan, Meital, Haugen, Eric, He, Yupeng, Heimfeld, Shelly, Herlofsen, Sarah, Hou, Zhonggang, Humbert, Richard, Issner, Robbyn, Jackson, Andrew R., Jia, Haiyang, Jiang, Peng, Johnson, Audra K., Kadlecek, Theresa, Kamoh, Baljit, Kapidzic, Mirhan, Kent, Jim, Kim, Audrey, Kleinewietfeld, Markus, Klugman, Sarit, Krishnan, Jayanth, Kuan, Samantha, Kutyavin, Tanya, Lee, Ah-Young, Lee, Kristen, Li, Jian, Li, Nan, Li, Yan, Ligon, Keith L., Lin, Shin, Lin, Yiing, Liu, Jie, Liu, Yuxuan, Luckey, John C., Ma, Yussanne P., Maire, Cecile, Marson, Alexander, Mattick, John S., Mayo, Michael, McMaster, Michael, Metsky, Hayden, Mikkelsen, Tarjei, Miller, Diane, Miri, Mohammad, Mukame, Eran, Nagarajan, Raman P., Neri, Fidencio, Nery, Joseph, Nguyen, Tung, OʼGeen, Henriette, Paithankar, Sameer, Papayannopoulou, Thalia, Pelizzola, Mattia, Plettner, Patrick, Propson, Nicholas E., Raghuraman, Sriram, Raney, Brian J., Raubitschek, Anthony, Reynolds, Alex P., Richards, Hunter, Riehle, Kevin, Rinaudo, Paolo, Robinson, Joshua F., Rockweiler, Nicole B., Rosen, Evan, Rynes, Eric, Schein, Jacqueline, Sears, Renee, Sejnowski, Terrence, Shafer, Anthony, Shen, Li, Shoemaker, Robert, Sigaroudinia, Mahvash, Slukvin, Igor, Stehling-Sun, Sandra, Stewart, Ron, Subramanian, Sai Lakshmi, Suknuntha, Kran, Swanson, Scott, Tian, Shulan, Tilden, Hannah, Tsai, Linus, Urich, Mark, Vaughn, Ian, Vierstra, Jeff, Vong, Shinny, Wagner, Ulrich, Wang, Hao, Wang, Tao, Wang, Yunfei, Weiss, Arthur, Whitton, Holly, Wildberg, Andre, Witt, Heather, Won, Kyoung-Jae, Xie, Mingchao, Xing, Xiaoyun, Xu, Iris, Xuan, Zhenyu, Ye, Zhen, Yen, Chia-an, Yu, Pengzhi, Zhang, Xian, Zhang, Xiaolan, Zhao, Jianxin, Zhou, Yan, Zhu, Jiang, Zhu, Yun, Ziegler, Steven, Beaudet, Arthur E., Farnham, Peggy J., Haussler, David, Jones, Steven J. M., Marra, Marco A., Thomson, James A., Tsai, Li-Huei, Zhang, Michael Q., Chadwick, Lisa H., Bernstein, Bradley E., Ecker, Joseph R., Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, and Kellis, Manolis

Published
2015
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29. The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models

Author

Rozowsky, Joel, primary, Drenkow, Jorg, additional, Yang, Yucheng T, additional, Gursoy, Gamze, additional, Galeev, Timur, additional, Borsari, Beatrice, additional, Epstein, Charles B, additional, Xiong, Kun, additional, Xu, Jinrui, additional, Gao, Jiahao, additional, Yu, Keyang, additional, Berthel, Ana, additional, Chen, Zhanlin, additional, Navarro, Fabio, additional, Liu, Jason, additional, Sun, Maxwell S, additional, Wright, James, additional, Chang, Justin, additional, Cameron, Christopher JF, additional, Shoresh, Noam, additional, Gaskell, Elizabeth, additional, Adrian, Jessika, additional, Aganezov, Sergey, additional, Aguet, François, additional, Balderrama-Gutierrez, Gabriela, additional, Banskota, Samridhi, additional, Corona, Guillermo Barreto, additional, Chee, Sora, additional, Chhetri, Surya B, additional, Cortez Martins, Gabriel Conte, additional, Danyko, Cassidy, additional, Davis, Carrie A, additional, Farid, Daniel, additional, Farrell, Nina P, additional, Gabdank, Idan, additional, Gofin, Yoel, additional, Gorkin, David U, additional, Gu, Mengting, additional, Hecht, Vivian, additional, Hitz, Benjamin C, additional, Issner, Robbyn, additional, Kirsche, Melanie, additional, Kong, Xiangmeng, additional, Lam, Bonita R, additional, Li, Shantao, additional, Li, Bian, additional, Li, Tianxiao, additional, Li, Xiqi, additional, Lin, Khine Zin, additional, Luo, Ruibang, additional, Mackiewicz, Mark, additional, Moore, Jill E, additional, Mudge, Jonathan, additional, Nelson, Nicholas, additional, Nusbaum, Chad, additional, Popov, Ioann, additional, Pratt, Henry E, additional, Qiu, Yunjiang, additional, Ramakrishnan, Srividya, additional, Raymond, Joe, additional, Salichos, Leonidas, additional, Scavelli, Alexandra, additional, Schreiber, Jacob M, additional, Sedlazeck, Fritz J, additional, See, Lei Hoon, additional, Sherman, Rachel M, additional, Shi, Xu, additional, Shi, Minyi, additional, Sloan, Cricket Alicia, additional, Strattan, J Seth, additional, Tan, Zhen, additional, Tanaka, Forrest Y, additional, Vlasova, Anna, additional, Wang, Jun, additional, Werner, Jonathan, additional, Williams, Brian, additional, Xu, Min, additional, Yan, Chengfei, additional, Yu, Lu, additional, Zaleski, Christopher, additional, Zhang, Jing, additional, Ardlie, Kristin, additional, Cherry, J Michael, additional, Mendenhall, Eric M, additional, Noble, William S, additional, Weng, Zhiping, additional, Levine, Morgan E, additional, Dobin, Alexander, additional, Wold, Barbara, additional, Mortazavi, Ali, additional, Ren, Bing, additional, Gillis, Jesse, additional, Myers, Richard M, additional, Snyder, Michael P, additional, Choudhary, Jyoti, additional, Milosavljevic, Aleksandar, additional, Schatz, Michael C, additional, Guigó, Roderic, additional, Bernstein, Bradley E, additional, Gingeras, Thomas R, additional, and Gerstein, Mark, additional

Published
2021
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30. Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer

Author

Johnstone, Sarah E., primary, Reyes, Alejandro, additional, Qi, Yifeng, additional, Adriaens, Carmen, additional, Hegazi, Esmat, additional, Pelka, Karin, additional, Chen, Jonathan H., additional, Zou, Luli S., additional, Drier, Yotam, additional, Hecht, Vivian, additional, Shoresh, Noam, additional, Selig, Martin K., additional, Lareau, Caleb A., additional, Iyer, Sowmya, additional, Nguyen, Son C., additional, Joyce, Eric F., additional, Hacohen, Nir, additional, Irizarry, Rafael A., additional, Zhang, Bin, additional, Aryee, Martin J., additional, and Bernstein, Bradley E., additional

Published
2020
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34. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

Author

Yizhak, Keren, primary, Aguet, François, additional, Kim, Jaegil, additional, Hess, Julian M., additional, Kübler, Kirsten, additional, Grimsby, Jonna, additional, Frazer, Ruslana, additional, Zhang, Hailei, additional, Haradhvala, Nicholas J., additional, Rosebrock, Daniel, additional, Livitz, Dimitri, additional, Li, Xiao, additional, Arich-Landkof, Eila, additional, Shoresh, Noam, additional, Stewart, Chip, additional, Segrè, Ayellet V., additional, Branton, Philip A., additional, Polak, Paz, additional, Ardlie, Kristin G., additional, and Getz, Gad, additional

Published
2019
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35. A comprehensive analysis of RNA sequences reveals macroscopic somatic clonal expansion across normal tissues

Author

Yizhak, Keren, primary, Aguet, Francois, additional, Kim, Jaegil, additional, Hess, Julian, additional, Kubler, Kirsten, additional, Grimsby, Jonna, additional, Frazer, Ruslana, additional, Zhang, Hailei, additional, Haradhvala, Nicholas J., additional, Rosebrock, Daniel, additional, Livitz, Dimitri, additional, Li, Xiao, additional, Landkof, Eila-Arich, additional, Shoresh, Noam, additional, Stewart, Chip, additional, Segre, Ayelet, additional, Branton, Philip A., additional, Polak, Paz, additional, Ardlie, Kristin, additional, and Getz, Gad, additional

Published
2018
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36. Defining the core essential genome ofPseudomonas aeruginosa

Author

Poulsen, Bradley E., primary, Yang, Rui, additional, Clatworthy, Anne E., additional, White, Tiantian, additional, Osmulski, Sarah J., additional, Li, Li, additional, Penaranda, Cristina, additional, Lander, Eric S., additional, Shoresh, Noam, additional, and Hung, Deborah T., additional

Published
2018
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37. Abstract LB-231: Identifying cancer-related processes in normal tissues via RNA-seq

Author

Yizhak, Keren, primary, Kim, Jaegil, additional, Aguet, Francois, additional, Hess, Julian, additional, Zhang, Hailei, additional, Arich-Landkof, Eila, additional, Shoresh, Noam, additional, Segre, Ayelet, additional, Stewart, Chip, additional, Rosebrock, Dainel, additional, Livitz, Dimitri, additional, Haradhvala, Nicholas, additional, Polak, Paz, additional, Sullivan, Tim, additional, Li, Xiao, additional, Ardlie, Kristin, additional, and Getz, Gad, additional

Published
2017
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38. A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

Author

Gupta, Rajat M., primary, Hadaya, Joseph, additional, Trehan, Aditi, additional, Zekavat, Seyedeh M., additional, Roselli, Carolina, additional, Klarin, Derek, additional, Emdin, Connor A., additional, Hilvering, Catharina R.E., additional, Bianchi, Valerio, additional, Mueller, Christian, additional, Khera, Amit V., additional, Ryan, Russell J.H., additional, Engreitz, Jesse M., additional, Issner, Robbyn, additional, Shoresh, Noam, additional, Epstein, Charles B., additional, de Laat, Wouter, additional, Brown, Jonathan D., additional, Schnabel, Renate B., additional, Bernstein, Bradley E., additional, and Kathiresan, Sekar, additional

Published
2017
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42. Genetic and epigenetic fine mapping of causal autoimmune disease variants

Author

Farh, Kyle Kai-How, primary, Marson, Alexander, additional, Zhu, Jiang, additional, Kleinewietfeld, Markus, additional, Housley, William J., additional, Beik, Samantha, additional, Shoresh, Noam, additional, Whitton, Holly, additional, Ryan, Russell J. H., additional, Shishkin, Alexander A., additional, Hatan, Meital, additional, Carrasco-Alfonso, Marlene J., additional, Mayer, Dita, additional, Luckey, C. John, additional, Patsopoulos, Nikolaos A., additional, De Jager, Philip L., additional, Kuchroo, Vijay K., additional, Epstein, Charles B., additional, Daly, Mark J., additional, Hafler, David A., additional, and Bernstein, Bradley E., additional

Published
2014
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43. Integrative analysis of 111 reference human epigenomes

Author

Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Kheradpour, Pouya, Zhang, Zhizhuo, Heravi-Moussavi, Alireza, Liu, Yaping, Amin, Viren, Ziller, Michael J, Whitaker, John W, Schultz, Matthew D, Sandstrom, Richard S, Eaton, Matthew L, Wu, Yi-Chieh, Wang, Jianrong, Ward, Lucas D, Sarkar, Abhishek, Quon, Gerald, Pfenning, Andreas, Wang, Xinchen, Claussnitzer, Melina, Coarfa, Cristian, Harris, R Alan, Shoresh, Noam, Epstein, Charles B, Gjoneska, Elizabeta, Leung, Danny, Xie, Wei, Hawkins, R David, Lister, Ryan, Hong, Chibo, Gascard, Philippe, Mungall, Andrew J, Moore, Richard, Chuah, Eric, Tam, Angela, Canfield, Theresa K, Hansen, R Scott, Kaul, Rajinder, Sabo, Peter J, Bansal, Mukul S, Carles, Annaick, Dixon, Jesse R, Farh, Kai-How, Feizi, Soheil, Karlic, Rosa, Kim, Ah-Ram, Kulkarni, Ashwinikumar, Li, Daofeng, Lowdon, Rebecca, Mercer, Tim R, Neph, Shane J, Onuchic, Vitor, Polak, Paz, Rajagopal, Nisha, Ray, Pradipta, Sallari, Richard C, Siebenthall, Kyle T, Sinnott-Armstrong, Nicholas, Stevens, Michael, Thurman, Robert E, Wu, Jie, Zhang, Bo, Zhou, Xin, Beaudet, Arthur E, Boyer, Laurie A, De Jager, Philip, Farnham, Peggy J, Fisher, Susan J, Haussler, David, Jones, Steven, Li, Wei, Marra, Marco, McManus, Michael T, Sunyaev, Shamil, Thomson, James A, Tlsty, Thea D, Tsai, Li-Huei, Wang, Wei, Waterland, Robert A, Zhang, Michael, Chadwick, Lisa H, Bernstein, Bradley E, Costello, Joseph F, Ecker, Joseph R, Hirst, Martin, Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, Stamatoyannopoulos, John A, Wang, Ting, and Kellis, Manolis

Abstract

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but a similar reference has lacked for epigenomic studies. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection to-date of human epigenomes for primary cells and tissues. Here, we describe the integrative analysis of 111 reference human epigenomes generated as part of the program, profiled for histone modification patterns, DNA accessibility, DNA methylation, and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically-relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation, and human disease.

Published
2015
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44. Perturbation-Specific Transcriptional Mapping for unbiased target elucidation of antibiotics.

Author

Romano KP, Bagnall J, Warrier T, Sullivan J, Ferrara K, Orzechowski M, Nguyen P, Raines K, Livny J, Shoresh N, and Hung D

Abstract

The rising prevalence of antibiotic resistance threatens human health. While more sophisticated strategies for antibiotic discovery are being developed, target elucidation of new chemical entities remains challenging. In the post-genomic era, expression profiling can play an important role in mechanism-of-action (MOA) prediction by reporting on the cellular response to perturbation. However, the broad application of transcriptomics has yet to fulfill its promise of transforming target elucidation due to challenges in identifying the most relevant, direct responses to target inhibition. We developed an unbiased strategy for MOA prediction, called Perturbation-Specific Transcriptional Mapping (PerSpecTM), in which large-throughput expression profiling of wildtype or hypomorphic mutants, depleted for essential targets, enables a computational strategy to address this challenge. We applied PerSpecTM to perform reference-based MOA prediction based on the principle that similar perturbations, whether chemical or genetic, will elicit similar transcriptional responses. Using this approach, we elucidated the MOAs of three new molecules with activity against Pseudomonas aeruginosa by comparing their expression profiles to those of a reference set of antimicrobial compounds with known MOAs. We also show that transcriptional responses to small molecule inhibition resemble those resulting from genetic depletion of essential targets by CRISPRi by PerSpecTM, demonstrating proof-of-concept that correlations between expression profiles of small molecule and genetic perturbations can facilitate MOA prediction when no chemical entities exist to serve as a reference. Empowered by PerSpecTM, this work lays the foundation for an unbiased, readily scalable, systematic reference-based strategy for MOA elucidation that could transform antibiotic discovery efforts.

Published
2024
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45. "Multiplexed screen identifies a Pseudomonas aeruginosa -specific small molecule targeting the outer membrane protein OprH and its interaction with LPS".

Author

Poulsen BE, Warrier T, Barkho S, Bagnall J, Romano KP, White T, Yu X, Kawate T, Nguyen PH, Raines K, Ferrara K, Golas A, Fitzgerald M, Boeszoermenyi A, Kaushik V, Serrano-Wu M, Shoresh N, and Hung DT

Abstract

The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa , a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT 1 , a target-based, whole-cell screening strategy, to discover small molecule probes that kill P. aeruginosa mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a P. aeruginosa mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM β-barrel protein OprH to disrupt its interaction with LPS and increase membrane fluidity. Studies with BRD1401 also revealed an interaction between OprL and OprH, directly linking the OM with peptidoglycan. Thus, a whole-cell, multiplexed screen can identify species-specific chemical probes to reveal novel pathogen biology.

Published
2024
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46. Single-cell multi-scale footprinting reveals the modular organization of DNA regulatory elements.

Author

Hu Y, Ma S, Kartha VK, Duarte FM, Horlbeck M, Zhang R, Shrestha R, Labade A, Kletzien H, Meliki A, Castillo A, Durand N, Mattei E, Anderson LJ, Tay T, Earl AS, Shoresh N, Epstein CB, Wagers A, and Buenrostro JD

Abstract

Cis -regulatory elements control gene expression and are dynamic in their structure, reflecting changes to the composition of diverse effector proteins over time 1-3 . Here we sought to connect the structural changes at cis- regulatory elements to alterations in cellular fate and function. To do this we developed PRINT, a computational method that uses deep learning to correct sequence bias in chromatin accessibility data and identifies multi-scale footprints of DNA-protein interactions. We find that multi-scale footprints enable more accurate inference of TF and nucleosome binding. Using PRINT with single-cell multi-omics, we discover wide-spread changes to the structure and function of candidate cis -regulatory elements (cCREs) across hematopoiesis, wherein nucleosomes slide, expose DNA for TF binding, and promote gene expression. Activity segmentation using the co-variance across cell states identifies "sub-cCREs" as modular cCRE subunits of regulatory DNA. We apply this single-cell and PRINT approach to characterize the age-associated alterations to cCREs within hematopoietic stem cells (HSCs). Remarkably, we find a spectrum of aging alterations among HSCs corresponding to a global gain of sub-cCRE activity while preserving cCRE accessibility. Collectively, we reveal the functional importance of cCRE structure across cell states, highlighting changes to gene regulation at single-cell and single-base-pair resolution., Competing Interests: Declaration of Interests J. Buenrostro holds patents related to ATAC-seq and is an SAB member of Camp4 and seqWell. J. Buenrostro and S. Ma holds a patent based on SHARE-seq. A.J.W. is a scientific advisor for Frequency Therapeutics and Kate Therapeutics. A.J.W. is also a co-founder and scientific advisory board member and holds private equity in Elevian, Inc., a company that aims to develop medicines to restore regenerative capacity. Elevian also provides sponsored research to the Wagers lab.

Published
2023
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