DNA sequence and chromatin modifiers cooperate to confer epigenetic bistability at imprinting control regions
Butz, Stefan; Schmolka, Nina; Karemaker, Ino; Villaseñor, Rodrigo; Schwarz, Isabel; Domcke, Silvia; Uijttewaal, Esther C. H.; Jude, Julian; Lienert, Florian; Krebs, Arnaud; Wagenaar, Nathalie P. de; Bao, Xue; Zuber, Johannes; Elling, Ulrich; Schübeler, Dirk; Baubec, Tuncay
(2022) Nature Genetics, volume 54, issue 11, pp. 1702 - 1710
(Article)
Abstract
Genomic imprinting is regulated by parental-specific DNA methylation of imprinting control regions (ICRs). Despite an identical DNA sequence, ICRs can exist in two distinct epigenetic states that are memorized throughout unlimited cell divisions and reset during germline formation. Here, we systematically study the genetic and epigenetic determinants of this epigenetic
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bistability. By iterative integration of ICRs and related DNA sequences to an ectopic location in the mouse genome, we first identify the DNA sequence features required for maintenance of epigenetic states in embryonic stem cells. The autonomous regulatory properties of ICRs further enabled us to create DNA-methylation-sensitive reporters and to screen for key components involved in regulating their epigenetic memory. Besides DNMT1, UHRF1 and ZFP57, we identify factors that prevent switching from methylated to unmethylated states and show that two of these candidates, ATF7IP and ZMYM2, are important for the stability of DNA and H3K9 methylation at ICRs in embryonic stem cells.
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Keywords: Demethylation, Embryonic stem-cells, Expression, Gene, Ground-state, Heterochromatin formation, Identification, Methylation, Transcription, Zfp57, Genetics
ISSN: 1061-4036
Publisher: Nature Publishing Group
Note: Funding Information: We thank A. Dean (NIH/NIDDK) for kindly providing the TC-1 mESC line and M. Buehler (FMI Basel) and C. Földy (University of Zurich) for sharing plasmids. Furthermore, we thank G. Schwank and group (University of Zurich) for their help in establishing the CRISPR-screen protocol, the Functional Genomics Centre Zurich (FGCZ), S3IT Zurich, and Cytometry Facility at University of Zurich for their support. We thank P.-A. Defossez (Paris Diderot University) and members of the Baubec group for their input and for their constructive criticism. T.B. acknowledges support from the University of Zurich and Utrecht University, Swiss National Science Foundation (183722, 180354 and 190378), the European Research Council (865094 - ChromatinLEGO - ERC-2019-COG) and the EMBO Young Investigator program. N.S. was supported by postdoctoral fellowships from EMBO and University of Zurich and is an SNSF Ambizione grant fellow (186012). R.V. acknowledges support from the University of Zurich (UZH postdoctoral grant FK-21-060). D.S. acknowledges support from the Novartis Research Foundation, the European Research Council under the European Union’s (EU) Horizon 2020 research and innovation program grant agreement (667951-ReadMe and 884664-DNAccess) and the Swiss National Science Foundation (310030B_176394). A.R.K. acknowledges support from the European Molecular Biology Laboratory, Deutsche Forschungsgemeinschaft (KR 5247/1-1) and the Swiss National Fund Ambizione (grant PZOOP3_161493). Funding Information: We thank A. Dean (NIH/NIDDK) for kindly providing the TC-1 mESC line and M. Buehler (FMI Basel) and C. Földy (University of Zurich) for sharing plasmids. Furthermore, we thank G. Schwank and group (University of Zurich) for their help in establishing the CRISPR-screen protocol, the Functional Genomics Centre Zurich (FGCZ), S3IT Zurich, and Cytometry Facility at University of Zurich for their support. We thank P.-A. Defossez (Paris Diderot University) and members of the Baubec group for their input and for their constructive criticism. T.B. acknowledges support from the University of Zurich and Utrecht University, Swiss National Science Foundation (183722, 180354 and 190378), the European Research Council (865094 - ChromatinLEGO - ERC-2019-COG) and the EMBO Young Investigator program. N.S. was supported by postdoctoral fellowships from EMBO and University of Zurich and is an SNSF Ambizione grant fellow (186012). R.V. acknowledges support from the University of Zurich (UZH postdoctoral grant FK-21-060). D.S. acknowledges support from the Novartis Research Foundation, the European Research Council under the European Union’s (EU) Horizon 2020 research and innovation program grant agreement (667951-ReadMe and 884664-DNAccess) and the Swiss National Science Foundation (310030B_176394). A.R.K. acknowledges support from the European Molecular Biology Laboratory, Deutsche Forschungsgemeinschaft (KR 5247/1-1) and the Swiss National Fund Ambizione (grant PZOOP3_161493). Publisher Copyright: © 2022, The Author(s).
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