Polycomb complexes act redundantly to repress genomic repeats and genes

Leeb, Martin; Pasini, Diego; Novatchkova, Maria; Jaritz, Markus; Helin, Kristian; Wutz, Anton

doi:10.1101/gad.544410

Cited by 306 publications

(358 citation statements)

References 64 publications

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“…In Ring1b depleted mESCs only Sox2 levels were compromised while the expression of the other ES regulators remained unchanged in line with earlier reports. 49,50 Depletion of Med12 resulted in reduced levels of Oct4, Nanog and Sox2 in accordance with previous findings. 44 In addition we observed reduced levels of Klf4 in Med12 knockdown mESCs.…”

Section: Functions Of Ring1b Med12 and Cdk8 During Differentiationsupporting

confidence: 80%

“…EBs derived from Ring1b knockdown cells are relatively small and do not differentiate properly, which is in agreement with an earlier study. 50 Although we observed a similar phenotype when analyzing EBs derived from Med12 knockdown cell lines it appears that Ring1b and Med12 have different regulatory functions at developmental genes during differentiation. Whereas knockdown of Ring1b results in misregulation of germ layer marker genes, depletion of Med12 leads to strongly diminished activation of the same genes.…”

Section: Discussionmentioning

confidence: 73%

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Dual role of Med12 in PRC1-dependent gene repression and ncRNA-mediated transcriptional activation

et al. 2016

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Mediator is considered an enhancer of RNA-Polymerase II dependent transcription but its function and regulation in pluripotent mouse embryonic stem cells (mESCs) remains unresolved. One means of controlling the function of Mediator is provided by the binding of the Cdk8 module (Med12, Cdk8, Ccnc and Med13) to the core Mediator. Here we report that Med12 operates together with PRC1 to silence key developmental genes in pluripotency. At the molecular level, while PRC1 represses genes it is also required to assemble ncRNA containing Med12-Mediator complexes. In the course of cellular differentiation the H2A ubiquitin binding protein Zrf1 abrogates PRC1-Med12 binding and facilitates the association of Cdk8 with Mediator. This remodeling of Mediator-associated protein complexes converts Mediator from a transcriptional repressor to a transcriptional enhancer, which then mediates ncRNA-dependent activation of Polycomb target genes. Altogether, our data reveal how the interplay of PRC1, ncRNA and Mediator complexes controls pluripotency and cellular differentiation.

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Section: Functions Of Ring1b Med12 and Cdk8 During Differentiationsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 73%

Dual role of Med12 in PRC1-dependent gene repression and ncRNA-mediated transcriptional activation

et al. 2016

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“…Similar to the case of DNA methylation, loss of Polycomb proteins Eed and Ring1b does not influence the self-renewal properties of ES cells. However, a loss of Polycomb destabilizes ES cells due to expression of lineage-specific markers (Leeb and Wutz 2007;Chamberlain et al 2008;Leeb et al 2010). Taken together, these findings suggest that transcriptional repression is not essential for pluripotency.…”

Section: Discussionsupporting

confidence: 55%

Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis

Bogdanović

Long²,

Heeringen³

et al. 2011

Genome Res.

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DNA methylation is a tightly regulated epigenetic mark associated with transcriptional repression. Next-generation sequencing of purified methylated DNA obtained from early Xenopus tropicalis embryos demonstrates that this genome is heavily methylated during blastula and gastrula stages. Although DNA methylation is largely absent from transcriptional start sites marked with histone H3 lysine 4 trimethylation (H3K4me3), we find both promoters and gene bodies of active genes robustly methylated. In contrast, DNA methylation is absent in large H3K27me3 domains, indicating that these two repression pathways have different roles. Comparison with chromatin state maps of human ES cells reveals strong conservation of epigenetic makeup and gene regulation between the two systems. Strikingly, genes that are highly expressed in pluripotent cells and in Xenopus embryos but not in differentiated cells exhibit relatively high DNA methylation. Therefore, we tested the repressive potential of DNA methylation using transient and transgenic approaches and show that methylated promoters are robustly transcribed in blastula-and gastrula-stage embryos, but not in oocytes or late embryos. These findings have implications for reprogramming and the epigenetic regulation of pluripotency and differentiation and suggest a relatively open, pliable chromatin state in early embryos followed by reestablished methylation-dependent transcriptional repression during organogenesis and differentiation.

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“…Combined loss of H3K9 and H4K20 trimethylation can induce the reactivation of L1 elements, as was observed in mouse fibroblasts lacking the heterochromatin-associated retinoblastoma protein (Montoya-Durango et al, 2009). Finally, the repressive mark H3K27 trimethylation probably has a role in silencing TEs, as combined inactivation of the polycomb complexes PRC1 and PRC2 leads to an upregulation of LTR-sequences in ES cells (Leeb et al, 2010).…”

Section: Host Responses To Tes or How To Live With A Herd Of Squattersmentioning

confidence: 98%

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

2010

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Retrotransposable elements comprise around 50% of the mammalian genome. Their activity represents a constant threat to the host and has prompted the development of adaptive control mechanisms to protect genome architecture and function. To ensure their propagation, retrotransposons have to mobilize in cells destined for the next generation. Accordingly, these elements are particularly well suited to transcriptional networks associated with pluripotent and germinal states in mammals. The relaxation of epigenetic control that occurs in the early developing germline constitutes a dangerous window in which retrotransposons can escape from host restraint and massively expand. What could be observed as risky behavior may turn out to be an insidious strategy developed by germ cells to sense retrotransposons and hold them back in check. Herein, we review recent insights that have provided a detailed picture of the defense mechanisms that concur toward retrotransposon silencing in mammalian genomes, and in particular in the germline. In this lineage, retrotransposons are hit at multiple stages of their life cycle, through transcriptional repression, RNA degradation and translational control. An organized cross-talk between PIWIinteracting small RNAs (piRNAs) and various nuclear and cytoplasmic accessories provides this potent and multilayered response to retrotransposon unleashing in early germ cells.

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Polycomb complexes act redundantly to repress genomic repeats and genes

Cited by 306 publications

References 64 publications

Dual role of Med12 in PRC1-dependent gene repression and ncRNA-mediated transcriptional activation

Dual role of Med12 in PRC1-dependent gene repression and ncRNA-mediated transcriptional activation

Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

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