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8 results on '"Liana Goehring"'

1. KMT2C/KMT2D-dependent H3K4me1 mediates changes in DNA replication timing and origin activity during a cell fate transition

Author

Deniz Gökbuget, Liana Goehring, Ryan M. Boileau, Kayla Lenshoek, Tony T. Huang, and Robert Blelloch

Subjects
CP: Molecular biology, Biology (General), QH301-705.5
Abstract

Summary: Mammalian genomes replicate in a cell-type-specific order during the S phase, correlated to transcriptional activity, histone modifications, and chromatin structure. The causal relationships between these features and DNA replication timing (RT), especially during cell fate changes, are largely unknown. Using machine learning, we quantify 21 chromatin features predicting local RT and RT changes during differentiation in embryonic stem cells (ESCs). About one-third of the genome shows RT changes during differentiation. Chromatin features accurately predict both steady-state RT and RT changes. Histone H3 lysine 4 monomethylation (H3K4me1), catalyzed by KMT2C and KMT2D (KMT2C/D), emerges as a top predictor. Loss of KMT2C/D or their enzymatic activities impairs RT changes during differentiation. This correlates with local H3K4me1 loss and reduced replication origin firing, while transcription remains largely unaffected. Our findings reveal KMT2C/D-dependent H3K4me1 as a key regulator of RT and replication initiation, a role that likely impacts diseases associated with KMT2C/D mutations. more...

Published
2025
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2. Dormant origin firing promotes head-on transcription-replication conflicts at transcription termination sites in response to BRCA2 deficiency

Author

Liana Goehring, Sarah Keegan, Sudipta Lahiri, Wenxin Xia, Michael Kong, Judit Jimenez-Sainz, Dipika Gupta, Ronny Drapkin, Ryan B. Jensen, Duncan J. Smith, Eli Rothenberg, David Fenyö, and Tony T. Huang more...

Subjects
Science
Abstract

Abstract BRCA2 is a tumor suppressor protein responsible for safeguarding the cellular genome from replication stress and genotoxicity, but the specific mechanism(s) by which this is achieved to prevent early oncogenesis remains unclear. Here, we provide evidence that BRCA2 acts as a critical suppressor of head-on transcription-replication conflicts (HO-TRCs). Using Okazaki-fragment sequencing (Ok-seq) and computational analysis, we identified origins (dormant origins) that are activated near the transcription termination sites (TTS) of highly expressed, long genes in response to replication stress. Dormant origins are a source for HO-TRCs, and drug treatments that inhibit dormant origin firing led to a reduction in HO-TRCs, R-loop formation, and DNA damage. Using super-resolution microscopy, we showed that HO-TRC events track with elongating RNA polymerase II, but not with transcription initiation. Importantly, RNase H2 is recruited to sites of HO-TRCs in a BRCA2-dependent manner to help alleviate toxic R-loops associated with HO-TRCs. Collectively, our results provide a mechanistic basis for how BRCA2 shields against genomic instability by preventing HO-TRCs through both direct and indirect means occurring at predetermined genomic sites based on the pre-cancer transcriptome. more...

Published
2024
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3. WEE1i-ATRi combination therapy: a promising low-dose treatment for CCNE1-amplified gynecologic cancers

Author

Liana Goehring and Tony T. Huang

Subjects
Medicine (General), R5-920
Abstract

CCNE1 amplification is an oncogenic driver for many gynecologic cancers and is associated with poor patient outcomes. In this issue, Xu et al.1 identify a combination therapy that is responsive to high CCNE1-copy number ovarian and endometrial cancers using PDX models. more...

Published
2021
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4. A reference map of the human binary protein interactome.

Author

Katja Luck, Dae-Kyum Kim, Luke Lambourne, Kerstin Spirohn, Bridget E. Begg, Wenting Bian, Ruth Brignall, Tiziana Cafarelli, Francisco J. Campos-Laborie, Benoît Charloteaux, Dong-Sic Choi, Atina G. Coté, Meaghan Daley, Steven Deimling, Alice Desbuleux, Amélie Dricot, Marinella Gebbia, Madeleine F. Hardy, Nishka Kishore, Jennifer J. Knapp, István A. Kovács, Irma Lemmens, Miles W. Mee, Joseph C. Mellor, Carl Pollis, Carles Pons, Aaron D. Richardson, Sadie Schlabach, Bridget Teeking, Anupama Yadav, Mariana Babor, Dawit Balcha, Omer Basha, Christian Bowman-Colin, Suet-Feung Chin, Soon-gang Choi, Claudia Colabella, Georges Coppin, Cassandra D'Amata, David De Ridder, Steffi De Rouck, Miquel Duran-Frigola, Hanane Ennajdaoui, Florian Goebels, Liana Goehring, Anjali Gopal, Ghazal Haddad, Elodie Hatchi, Mohamed Helmy, Yves Jacob, Yoseph Kassa, Serena Landini, Roujia Li, Natascha van Lieshout, Andrew MacWilliams, Dylan Markey, Joseph N. Paulson, Sudharshan Rangarajan, John Rasla, Ashyad Rayhan, Thomas Rolland, Adriana San-Miguel, Yun Shen, Dayag Sheykhkarimli, Gloria M. Sheynkman, Eyal Simonovsky, Murat Tasan, Alexander Tejeda, Vincent Tropepe, Jean-Claude Twizere, Yang Wang 0081, Robert J. Weatheritt, Jochen Weile, Yu Xia 0002, Xinping Yang, Esti Yeger Lotem, Quan Zhong, Patrick Aloy, Gary D. Bader, Javier De Las Rivas, Suzanne Gaudet, Tong Hao, Janusz Rak, Jan Tavernier, David E. Hill, Marc Vidal, Frederick P. Roth, and Michael A. Calderwood more...

Published
2020
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5. BRCA1 and RNAi factors promote repair mediated by small RNAs and PALB2–RAD52

Author

Timothy M. Demers, Liana Goehring, Elodie Hatchi, Yaoyu E. Wang, Derrick K. DeConti, Priyankana Banerjee, Fieda Abderazzaq, Serena Landini, David M. Livingston, Konstantina Skourti-Stathaki, and John Quackenbush more...

Subjects
Genome instability, 0303 health sciences, Small RNA, Multidisciplinary, DNA repair, RAD52, RNA, Biology, Genome, Cell biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, RNA interference, 030217 neurology & neurosurgery, DNA, 030304 developmental biology
Abstract

Strong connections exist between R-loops (three-stranded structures harbouring an RNA:DNA hybrid and a displaced single-strand DNA), genome instability and human disease1–5. Indeed, R-loops are favoured in relevant genomic regions as regulators of certain physiological processes through which homeostasis is typically maintained. For example, transcription termination pause sites regulated by R-loops can induce the synthesis of antisense transcripts that enable the formation of local, RNA interference (RNAi)-driven heterochromation6. Pause sites are also protected against endogenous single-stranded DNA breaks by BRCA17. Hypotheses about how DNA repair is enacted at pause sites include a role for RNA, which is emerging as a normal, albeit unexplained, regulator of genome integrity8. Here we report that a species of single-stranded, DNA-damage-associated small RNA (sdRNA) is generated by a BRCA1–RNAi protein complex. sdRNAs promote DNA repair driven by the PALB2–RAD52 complex at transcriptional termination pause sites that form R-loops and are rich in single-stranded DNA breaks. sdRNA repair operates in both quiescent (G0) and proliferating cells. Thus, sdRNA repair can occur in intact tissue and/or stem cells, and may contribute to tumour suppression mediated by BRCA1. Single-stranded, DNA-damage-associated small RNAs generated by a BRCA1–RNA-interference complex promote PALB2–RAD52-mediated DNA repair at transcriptional termination pause sites that contain R-loops and are rich in single-stranded DNA breaks in both quiescent and proliferating cells. more...

Published
2021
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6. BRCA1 binds TERRA RNA and suppresses R-Loop-based telomeric DNA damage

Author

Mai Huynh, Jekaterina Vohhodina, Vladimir V. Botchkarev, Elodie Hatchi, Fieda Abderazzaq, Scott B. Ficarro, Zhiqi Liu, Qing Kong, Jarrod A. Marto, Liana Goehring, Ben Liu, David M. Livingston, and Allison P. Clark more...

Subjects
0301 basic medicine, Genome instability, endocrine system diseases, R-loop, General Physics and Astronomy, medicine.disease_cause, Mass Spectrometry, chemistry.chemical_compound, 0302 clinical medicine, RNA, Small Interfering, Promoter Regions, Genetic, skin and connective tissue diseases, In Situ Hybridization, Fluorescence, Mutation, Multidisciplinary, BRCA1 Protein, Cell Cycle, Telomere, Chromatin, Cell biology, Telomeres, 030220 oncology & carcinogenesis, RNA, Long Noncoding, RNA Helicases, Protein Binding, Genomic instability, Chromatin Immunoprecipitation, DNA repair, Science, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Cell Line, Tumor, medicine, Humans, DNA Helicases, RNA, Promoter, General Chemistry, Shelterin, Multifunctional Enzymes, 030104 developmental biology, chemistry, Exoribonucleases, Long non-coding RNAs, CpG Islands, Fragile sites, R-Loop Structures, DNA, Chromatography, Liquid, DNA Damage
Abstract

R-loop structures act as modulators of physiological processes such as transcription termination, gene regulation, and DNA repair. However, they can cause transcription-replication conflicts and give rise to genomic instability, particularly at telomeres, which are prone to forming DNA secondary structures. Here, we demonstrate that BRCA1 binds TERRA RNA, directly and physically via its N-terminal nuclear localization sequence, as well as telomere-specific shelterin proteins in an R-loop-, and a cell cycle-dependent manner. R-loop-driven BRCA1 binding to CpG-rich TERRA promoters represses TERRA transcription, prevents TERRA R-loop-associated damage, and promotes its repair, likely in association with SETX and XRN2. BRCA1 depletion upregulates TERRA expression, leading to overly abundant TERRA R-loops, telomeric replication stress, and signs of telomeric aberrancy. Moreover, BRCA1 mutations within the TERRA-binding region lead to an excess of TERRA-associated R-loops and telomeric abnormalities. Thus, normal BRCA1/TERRA binding suppresses telomere-centered genome instability., BRCA1-mediated resolution of R-loops has previously been described. Here the authors reveal a functional association of BRCA1 with TERRA RNA at telomeres, which develops in an R-loop-, and a cell cycle-dependent manner. more...

Published
2021
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7. A reference map of the human binary protein interactome

Author

Eyal Simonovsky, Joseph C. Mellor, Amélie Dricot, Marc Vidal, Liana Goehring, Miquel Duran-Frigola, Florian Goebels, Dayag Sheykhkarimli, Thomas Rolland, Murat Tasan, John Rasla, Steffi De Rouck, Carles Pons, Sadie Schlabach, Yoseph Kassa, Claudia Colabella, Dong-Sic Choi, Yves Jacob, Joseph N. Paulson, Javier De Las Rivas, Madeleine F. Hardy, Francisco J. Campos-Laborie, Xinping Yang, Soon Gang Choi, Frederick P. Roth, Kerstin Spirohn, Nishka Kishore, Luke Lambourne, Cassandra D’Amata, Dawit Balcha, Adriana San-Miguel, Anupama Yadav, Anjali Gopal, Suet-Feung Chin, Suzanne Gaudet, Yang Wang, István Kovács, Elodie Hatchi, Natascha van Lieshout, Michael A. Calderwood, Yu Xia, Gloria M. Sheynkman, Robert J. Weatheritt, Marinella Gebbia, Atina G. Cote, Bridget E. Begg, Mohamed Helmy, Katja Luck, Bridget Teeking, Quan Zhong, Serena Landini, David E. Hill, Sudharshan Rangarajan, Georges Coppin, Ghazal Haddad, Omer Basha, Carl Pollis, Dylan Markey, Alice Desbuleux, Hanane Ennajdaoui, Dae-Kyum Kim, Vincent Tropepe, Roujia Li, Steven Deimling, Jennifer J. Knapp, Jan Tavernier, Mariana Babor, Benoit Charloteaux, Gary D. Bader, Alexander O. Tejeda, Aaron Richardson, Ruth Brignall, Ashyad Rayhan, Irma Lemmens, Tong Hao, Christian Bowman-Colin, Janusz Rak, David De Ridder, Jochen Weile, Wenting Bian, Jean-Claude Twizere, Patrick Aloy, Esti Yeger-Lotem, Meaghan Daley, Tiziana M. Cafarelli, Andrew MacWilliams, Miles W. Mee, Yun Shen, National Institutes of Health (US), National Human Genome Research Institute (US), Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fonds de la Recherche Scientifique (Fédération Wallonie-Bruxelles), Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris], Dana-Farber Cancer Institute [Boston], Harvard Medical School [Boston] (HMS), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), University of Toronto, Mount Sinai Health System, Canadian Institute for Advanced Research (CIFAR), and This work was primarily supported by the National Institutes of Health (NIH) National Human Genome Research Institute (NHGRI) grant U41HG001715 (M.V., F.P.R., D.E.H., M.A.C., G.D.B. and J.T.) with additional support from NIH grants P50HG004233 (M.V. and F.P.R.), U01HL098166 (M.V.), U01HG007690 (M.V.), R01GM109199 (M.A.C.), Canadian Institute for Health Research (CIHR) Foundation Grants (F.P.R. and J. Rak), the Canada Excellence Research Chairs Program (F.P.R.) and an American Heart Association grant 15CVGPS23430000 (M.V.). D.-K.K. was supported by a Banting Postdoctoral Fellowship through the Natural Sciences and Engineering Research Council (NSERC) of Canada and by the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education (2017R1A6A3A03004385). C. Pons was supported by a Ramon Cajal fellowship (RYC-2017-22959). G.M.S. was supported by NIH Training Grant T32CA009361. M.V. is a Chercheur Qualifié Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium). more...

Subjects
0301 basic medicine, Multidisciplinary, Proteome, [SDV]Life Sciences [q-bio], Computational biology, Biology, Genome, Phenotype, Interactome, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Article, Protein–protein interaction, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Organ Specificity, Protein Interaction Mapping, Reference map, Humans, Cellular organization, Extracellular Space, 030217 neurology & neurosurgery, Function (biology)
Abstract

et al., Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks that mediate genotype–phenotype relationships1,2. Here we present a human ‘all-by-all’ reference interactome map of human binary protein interactions, or ‘HuRI’. With approximately 53,000 protein–protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. The integration of HuRI with genome3, transcriptome4 and proteome5 data enables cellular function to be studied within most physiological or pathological cellular contexts. We demonstrate the utility of HuRI in identifying the specific subcellular roles of protein–protein interactions. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms that might underlie tissue-specific phenotypes of Mendelian diseases. HuRI is a systematic proteome-wide reference that links genomic variation to phenotypic outcomes., This work was primarily supported by the National Institutes of Health (NIH) National Human Genome Research Institute (NHGRI) grant U41HG001715 (M.V., F.P.R., D.E.H., M.A.C., G.D.B. and J.T.) with additional support from NIH grants P50HG004233 (M.V. and F.P.R.), U01HL098166 (M.V.), U01HG007690 (M.V.), R01GM109199 (M.A.C.), Canadian Institute for Health Research (CIHR) Foundation Grants (F.P.R. and J. Rak), the Canada Excellence Research Chairs Program (F.P.R.) and an American Heart Association grant 15CVGPS23430000 (M.V.). D.-K.K. was supported by a Banting Postdoctoral Fellowship through the Natural Sciences and Engineering Research Council (NSERC) of Canada and by the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education (2017R1A6A3A03004385). C. Pons was supported by a Ramon Cajal fellowship (RYC-2017-22959). G.M.S. was supported by NIH Training Grant T32CA009361. M.V. is a Chercheurv Qualifié Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium). more...

Published
2020
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8. A reference map of the human protein interactome

Author

Madeleine F. Hardy, Bridget Teeking, Francisco J. Campos-Laborie, Dayag Sheykhkarimli, Dawit Balcha, Anjali Gopal, Marinella Gebbia, Ashyad Rayhan, Carles Pons, Gloria M. Sheynkman, Yves Jacob, Suzanne Gaudet, Aaron Richardson, Yoseph Kassa, Elodie Hatchi, Kerstin Spirohn, Dong-Sic Choi, Yu Xia, Eyal Simonovsky, David E. Hill, Hanane Ennajdaoui, Steven Deimling, Joseph N. Paulson, Natascha van Lieshout, Vincent Tropepe, Michael A. Calderwood, István Kovács, Gary D. Bader, Luke Lambourne, Sudharshan Rangarajan, Tiziana M. Cafarelli, Carl Pollis, Suet-Feung Chin, Alice Desbuleux, Andrew MacWilliams, Amélie Dricot, Jean-Claude Twizere, Patrick Aloy, Atina G. Cote, Marc Vidal, Jan Tavernier, Javier De Las Rivas, Cassandra D’Amata, Alexander O. Tejeda, Esti Yeger-Lotem, Liana Goehring, Joseph C. Mellor, Meaghan Daley, Irma Lemmens, Soon Gang Choi, Christian Bowman-Colin, Ghazal Haddad, Janusz Rak, Florian Goebels, Robert J. Weatheritt, Mariana Babor, Yang Wang, Thomas Rolland, Steffi De Rouck, Jochen Weile, Serena Landini, John Rasla, Sadie Schlabach, Nishka Kishore, Bridget E. Begg, Ruth Brignall, Quan Zhong, Tong Hao, David De Ridder, Claudia Colabella, Frederick P. Roth, Anupama Yadav, Mohamed Helmy, Katja Luck, Omer Basha, Dae-Kyum Kim, Benoit Charloteaux, Georges Coppin, Dylan Markey, Roujia Li, Miquel Duran-Frigola, Adriana San-Miguel, Wenting Bian, Miles W. Mee, Jennifer J. Knapp, Yun Shen, Murat Tasan, Xinping Yang, Dana-Farber Cancer Institute [Boston], Division of Medical Physics in Radiology [Heidelberg], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Cancer Research UK Cambridge Institute (CRUK), University of Cambridge [UK] (CAM), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Harvard Medical School [Boston] (HMS), University of Toronto, Universidad de Salamanca, McGill University Health Center [Montreal] (MUHC), Mount Sinai Hospital [Toronto, Canada] (MSH), Université de Liège, Wigner Research Centre for Physics [Budapest], Hungarian Academy of Sciences (MTA), Northeastern University [Boston], Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Universiteit Gent = Ghent University [Belgium] (UGENT), Barcelona Institute of Science and Technology (BIST), Ben-Gurion University of the Negev (BGU), Università degli Studi di Perugia (UNIPG), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Canadian Institute for Advanced Research (CIFAR), Universiteit Gent = Ghent University (UGENT), Università degli Studi di Perugia = University of Perugia (UNIPG), and Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS) more...

Subjects
0303 health sciences, Context (language use), Computational biology, Biology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Genome, Interactome, Human genetics, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Human interactome, Proteome, 030217 neurology & neurosurgery, Function (biology), 030304 developmental biology
Abstract

Global insights into cellular organization and function require comprehensive understanding of interactome networks. Similar to how a reference genome sequence revolutionized human genetics, a reference map of the human interactome network is critical to fully understand genotype-phenotype relationships. Here we present the first human “all-by-all” binary reference interactome map, or “HuRI”. With ~53,000 high-quality protein-protein interactions (PPIs), HuRI is approximately four times larger than the information curated from small-scale studies available in the literature. Integrating HuRI with genome, transcriptome and proteome data enables the study of cellular function within essentially any physiological or pathological cellular context. We demonstrate the use of HuRI in identifying specific subcellular roles of PPIs and protein function modulation via splicing during brain development. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms underlying tissue-specific phenotypes of Mendelian diseases. HuRI thus represents an unprecedented, systematic reference linking genomic variation to phenotypic outcomes. more...

Published
2019
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