Systematic identification of factors involved in the silencing of germline genes in mouse embryonic stem cells

Adhami, Hala Al; Vallet, Judith; Schaal, Celia; Schumacher, Petra B.; Bardet, Anaïs F.; Dumas, Michaël; Chicher, Johana; Hammann, Philippe; Daujat, Sylvain; Weber, Michaël

doi:10.1093/nar/gkad071

Cited by 9 publications

(5 citation statements)

References 91 publications

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“…We observe in mouse development and hESC systems that ERH is functionally required in multiple developmental contexts to repress meiotic and gametogenic genes, as it is in S. pombe 14 , although the gene members targeted by ERH in this pathway has evolved and expanded in mammals. Our findings on meiotic gene repression are supported by the recent identification of ERH in a screen for proteins silencing germline genes in mESCs 64 . Other aspects of Erh1 function in S. pombe, such as the targeting of RNAs for degradation by the RNA exosome 14 , appear to be conserved as we observed upregulation of developmental genes typically downregulated by RNA exosome degradation 25 .…”

Section: Discussionsupporting

confidence: 77%

Heterochromatin protein ERH represses alternative cell fates during early mammalian differentiation

Katznelson,

Hernandez,

Fahning

et al. 2024

Preprint

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SummaryDuring development, H3K9me3 heterochromatin is dynamically rearranged, silencing repeat elements and protein coding genes to restrict cell identity. Enhancer of Rudimentary Homolog (ERH) is an evolutionarily conserved protein originally characterized in fission yeast and recently shown to be required for H3K9me3 maintenance in human fibroblasts, but its function during development remains unknown. Here, we show that ERH is required for proper segregation of the inner cell mass and trophectoderm cell lineages during mouse development by repressing totipotent and alternative lineage programs. During human embryonic stem cell (hESC) differentiation into germ layer lineages, ERH is crucial for silencing naïve and pluripotency genes, transposable elements, and alternative lineage genes. Strikingly, ERH depletion in somatic cells reverts the H3K9me3 landscape to an hESC state and enables naïve and pluripotency gene and transposable element activation during iPSC reprogramming. Our findings reveal a role for ERH in initiation and maintenance of developmentally established gene repression.

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Section: Discussionsupporting

confidence: 77%

Heterochromatin protein ERH represses alternative cell fates during early mammalian differentiation

Katznelson,

Hernandez,

Fahning

et al. 2024

Preprint

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“…S14d) 66 . Most intriguingly, ncPRC1.6 is required for H3K27me3-to-5mC switching at a number of germline-specific gene promoters, although in these cases, the switch leads to maintained silencing 89,92,93 . It will be worthwhile to pursue a potential link between ncPRC1.6 and SWRs, and the possibility that ncPRC1.6 could facilitate gene activation via the same epigenetic switch mechanism that occurs at germline genes.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation shapes the Polycomb landscape during the exit from naïve pluripotency

Albert,

Urli,

Monteagudo-Sánchez

et al. 2023

Preprint

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In mammals, 5 methyl-cytosine (5mC) and Polycomb Repressive Complex 2 (PRC2)- deposited histone 3 lysine 27 trimethylation (H3K27me3) are generally mutually exclusive at CpG-rich regions. As mouse embryonic stem cells exit the naïve pluripotent state, there is a massive gain of 5mC coincident with a restriction of broad H3K27me3 to 5mC-free, CpG-rich regions. To formally assess how 5mC shapes the H3K27me3 landscape, we profiled the epigenome of naïve and differentiated cells in the presence and absence of the DNA methylation machinery. Surprisingly, we found that 5mC accumulation is not required to restrict most H3K27me3 domains. We went on to show that this 5mC-independent H3K27me3 restriction is mediated by aberrant expression of the PRC2 antagonistEzhip. At the regions where 5mC appears to genuinely supplant H3K27me3, we identified 68 candidate genes that appeared to require 5mC deposition and/or H3K27me3 depletion for their activation in differentiated cells. Employing site-directed epigenome editing to directly modulate 5mC levels, we demonstrated that 5mC deposition is sufficient to antagonize H3K27me3 deposition and confer gene activation at individual candidates. Altogether, we systematically measured the antagonistic interplay between 5mC and H3K27me3 in a system that recapitulates early embryonic dynamics. Our results suggest that H3K27me3 restraint depends on 5mC, both directly and indirectly. This study also reveals a non-canonical role of 5mC in gene activation, which may be important not only for normal development but also for cancer progression, as oncogenic cells frequently exhibit dynamic replacement of 5mC for H3K27me3 and vice versa.

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“…Notably, both in vivo and in the in vitro nESC-to-EpiLC differentiation model, de novo DNA methylation depends on this initial ncPRC1.6 and SETDB1 occupancy, whereas PRC2 is dispensible ( Fig. 4 C ; Mochizuki et al, 2021 ; Al Adhami et al, 2023 ; Dahlet et al, 2021 ). Despite previous reports suggesting DNMT3B being responsible for de novo DNA methylation at germline genes and that the ncPRC1.6 component E2F6 being responsible for its recruitment ( Velasco et al, 2010 ; Dahlet et al, 2021 ), another study demonstrated redundant roles for DNMT3A and DNMT3B ( Auclair et al, 2014 ).…”

Section: Crosstalk With Dna Methylation and H3k9 Methylationmentioning

confidence: 98%

Crosstalk within and beyond the Polycomb repressive system

Shi,

Sugishita,

Gotoh

2024

Journal of Cell Biology

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The development of multicellular organisms depends on spatiotemporally controlled differentiation of numerous cell types and their maintenance. To generate such diversity based on the invariant genetic information stored in DNA, epigenetic mechanisms, which are heritable changes in gene function that do not involve alterations to the underlying DNA sequence, are required to establish and maintain unique gene expression programs. Polycomb repressive complexes represent a paradigm of epigenetic regulation of developmentally regulated genes, and the roles of these complexes as well as the epigenetic marks they deposit, namely H3K27me3 and H2AK119ub, have been extensively studied. However, an emerging theme from recent studies is that not only the autonomous functions of the Polycomb repressive system, but also crosstalks of Polycomb with other epigenetic modifications, are important for gene regulation. In this review, we summarize how these crosstalk mechanisms have improved our understanding of Polycomb biology and how such knowledge could help with the design of cancer treatments that target the dysregulated epigenome.

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Systematic identification of factors involved in the silencing of germline genes in mouse embryonic stem cells

Cited by 9 publications

References 91 publications

Heterochromatin protein ERH represses alternative cell fates during early mammalian differentiation

Heterochromatin protein ERH represses alternative cell fates during early mammalian differentiation

DNA methylation shapes the Polycomb landscape during the exit from naïve pluripotency

Crosstalk within and beyond the Polycomb repressive system

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