Symmetric inheritance of parental histones governs epigenome maintenance and embryonic stem cell identity

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Modified parental histones are segregated symmetrically to daughter DNA strands during replication and can be inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here we show that transmission of histone-based information during DNA replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3–H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused derepression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Furthermore, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian cell differentiation.
OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind55
Udgave nummer9
Sider (fra-til)1567-1578
Antal sider12
ISSN1061-4036
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We thank J.M. Gonzalez and the reNEW Core Facility for Transgenic Mice for morula injections, M. Rothová, M. Linneberg-Agerholm and M. Perera Pérez for help with embryo dissection, N. Petryk for advice on SCAR-seq, Z. Jasencakova for help with model design, M. Michaut and H. Wollmann from the CPR/reNEW Genomics Platform for sequencing support and initial data processing, M. Bühler (Friedrich Miescher Institute for Biomedical Research (FMI), Switzerland) for TALEN acceptor and recombination reporter plasmids and S. Boulton (The Francis Crick Institute, UK) for sharing POLE4 antibodies. A.R.-R. was supported by a Ph.D. fellowship from the Lundbeck Foundation (R208-2015-2872). A.B. and V.F. were supported by Marie Curie Individual Fellowships (846375 and 841620). Research in the Andersson Laboratory is supported by the European Research Council (StG 638273), the Novo Nordisk Foundation (NNF18OC0052570, NNF20OC0059796 and NNF21SA0072102) and Independent Research Fund Denmark (6108-00038B). Research in the Brickman Laboratory is supported by the Lundbeck Foundation (R400-2022-769, R370-2021-617, and R198-2015-412), the Independent Research Fund Denmark (DFF-8020-00100B, DFF-0134-00022B and DFF-2034-00025B), the Danish National Research Foundation (DNRF116) and the Novo Nordisk Foundation (NNF21OC0070898). The Novo Nordisk Foundation Center for Stem Cell Medicine is supported by Novo Nordisk Foundation (grant number NNF21CC0073729 and previously NNF17CC0027852). Research in the Groth Laboratory is supported by the Lundbeck Foundation (R198-2015-269 and R313-2019-448), the European Research Council (ERC CoG 724436), Independent Research Fund Denmark (7016-00042B; 4092-00404B) and the Novo Nordisk Foundation (NNF21OC0067425). Research at CPR is supported by the Novo Nordisk Foundation (NNF14CC0001).

Funding Information:
We thank J.M. Gonzalez and the reNEW Core Facility for Transgenic Mice for morula injections, M. Rothová, M. Linneberg-Agerholm and M. Perera Pérez for help with embryo dissection, N. Petryk for advice on SCAR-seq, Z. Jasencakova for help with model design, M. Michaut and H. Wollmann from the CPR/reNEW Genomics Platform for sequencing support and initial data processing, M. Bühler (Friedrich Miescher Institute for Biomedical Research (FMI), Switzerland) for TALEN acceptor and recombination reporter plasmids and S. Boulton (The Francis Crick Institute, UK) for sharing POLE4 antibodies. A.R.-R. was supported by a Ph.D. fellowship from the Lundbeck Foundation (R208-2015-2872). A.B. and V.F. were supported by Marie Curie Individual Fellowships (846375 and 841620). Research in the Andersson Laboratory is supported by the European Research Council (StG 638273), the Novo Nordisk Foundation (NNF18OC0052570, NNF20OC0059796 and NNF21SA0072102) and Independent Research Fund Denmark (6108-00038B). Research in the Brickman Laboratory is supported by the Lundbeck Foundation (R400-2022-769, R370-2021-617, and R198-2015-412), the Independent Research Fund Denmark (DFF-8020-00100B, DFF-0134-00022B and DFF-2034-00025B), the Danish National Research Foundation (DNRF116) and the Novo Nordisk Foundation (NNF21OC0070898). The Novo Nordisk Foundation Center for Stem Cell Medicine is supported by Novo Nordisk Foundation (grant number NNF21CC0073729 and previously NNF17CC0027852). Research in the Groth Laboratory is supported by the Lundbeck Foundation (R198-2015-269 and R313-2019-448), the European Research Council (ERC CoG 724436), Independent Research Fund Denmark (7016-00042B; 4092-00404B) and the Novo Nordisk Foundation (NNF21OC0067425). Research at CPR is supported by the Novo Nordisk Foundation (NNF14CC0001).

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© 2023, The Author(s).

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