scholarly journals Dynamical modeling of the H3K27 epigenetic landscape in mouse embryonic stem cells

2021 ◽  
Author(s):  
Kapil Newar ◽  
Eric Fanchon ◽  
Daniel Jost
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Target Genes ◽  
Quantitative Description ◽  
Embryonic Stem ◽  
Quantitative Agreement ◽  
Mouse Embryonic Stem Cells ◽  
Perfect Agreement ◽  
Polycomb Repressive Complex 2 ◽  
Role Of The Reader

The Polycomb system via the methylation of the lysine 27 of histone H3 (H3K27) plays central roles in the silencing of many lineage-specific genes during development. Recent experimental evidence suggested that the recruitment of histone modifying enzymes like the Polycomb repressive complex 2 (PRC2) at specific sites and their spreading capacities from these sites are key to the establishment and maintenance of a proper epigenomic landscape around Polycomb-target genes. Here, based on previous biochemical knowledge, we turned this hypothesis into a mathematical model that can predict the locus-specific distributions of H3K27 modifications. Within the biological context of mouse embryonic stem cells, our model showed quantitative agreement with experimental profiles of H3K27 acetylation and methylation around Polycomb-target genes in wild-type and mutants. In particular, we demonstrated the key role of the reader-writer module of PRC2 and of the competition between the binding of activating and repressing enzymes in shaping the H3K27 landscape around transcriptional start sites. The predicted dynamics of establishment and maintenance of the repressive trimethylated H3K27 state suggest a slow accumulation, in perfect agreement with experiments. Our approach represents a first step towards a quantitative description of PcG regulation in various cellular contexts and provides a generic framework to better characterize epigenetic regulation in normal or disease situations.

scholarly journals Prediction of Polycomb target genes in mouse embryonic stem cells

Genomics ◽  
2010 ◽  
Vol 96 (1) ◽  
pp. 17-26 ◽  
Author(s):  
Yingchun Liu ◽  
Zhen Shao ◽  
Guo-Cheng Yuan
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Target Genes ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells

scholarly journals Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells

2019 ◽  
Author(s):  
Matteo Perino ◽  
Guido van Mierlo ◽  
Sandra M.T. Wardle ◽  
Hendrik Marks ◽  
Gert Jan C. Veenstra
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Positive Feedback ◽  
Target Genes ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Minor Effect ◽  
List Type ◽  
Systematic Analysis ◽  
Chemical Inhibition

AbstractPolycomb Repressive Complex 2 (PRC2) plays an essential role in development by catalysing trimethylation of histone H3 lysine 27 (H3K27me3), resulting in gene repression. PRC2 consists of two sub-complexes, PRC2.1 and PRC2.2, in which the PRC2 core associates with distinct ancillary subunits such as MTF2 and JARID2, respectively. Both MTF2, present in PRC2.1, and JARID2, present in PRC2.2, play a role in core PRC2 recruitment to target genes in mouse embryonic stem cells (mESCs). However, it remains unclear how these distinct sub-complexes cooperate to establish Polycomb domains. Here, we combine a range of Polycomb mutant mESCs with chemical inhibition of PRC2 catalytic activity, to systematically dissect their relative contributions to PRC2 binding to target loci. We find that PRC2.1 and PRC2.2 mediate two distinct paths for recruitment, with mutually reinforced binding. Part of the cross-talk between PRC2.1 and PRC2.2 occurs via their catalytic product H3K27me3, which is bound by the PRC2 core-subunit EED, thereby mediating a positive feedback. Strikingly, removal of either JARID2 or H3K27me3 only has a minor effect on PRC2 recruitment, whereas their combined ablation largely attenuates PRC2 recruitment. This strongly suggests an unexpected redundancy between JARID2 and EED-H3K27me3-mediated recruitment of PRC2. Furthermore, we demonstrate that all core PRC2 recruitment occurs through the combined action of MTF2-mediated recruitment of PRC2.1 to DNA and PRC1-mediated recruitment of JARID2-containing PRC2.2. Both axes of binding are supported by EED-H3K27me3 positive feedback, but to a different degree. Finally, we provide evidence that PRC1 and PRC2 mutually reinforce reciprocal binding. Together, these data disentangle the interdependent and cooperative interactions between Polycomb complexes that are important to establish Polycomb repression at target sites.HighlightsSystematic analysis of Polycomb complex binding to target loci in mESCs using null mutations and chemical inhibition.PRC1, PRC2.1 and PRC2.2 are all mutually dependent for binding to chromatin, mediated in part by H3K27me3.PRC2.1 recruitment is dependent on MTF2PRC2.2 recruitment by JARID2 is dependent on PRC1 and largely redundant with recruitment by H3K27me3

scholarly journals ChIP-Seq and RNA-Seq Analyses Identify Components of the Wnt and Fgf Signaling Pathways as Prep1 Target Genes in Mouse Embryonic Stem Cells

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0122518 ◽  
Author(s):  
Audrey Laurent ◽  
Manuela Calabrese ◽  
Hans-Jörg Warnatz ◽  
Marie-Laure Yaspo ◽  
Vsevolod Tkachuk ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Signaling Pathways ◽  
Target Genes ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Rna Seq ◽  
Fgf Signaling

scholarly journals PCGF6-PRC1 suppresses premature differentiation of mouse embryonic stem cells by regulating germ cell-related genes

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Mitsuhiro Endoh ◽  
Takaho A Endo ◽  
Jun Shinga ◽  
Katsuhiko Hayashi ◽  
Anca Farcas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Germ Cell ◽  
Target Genes ◽  
Embryonic Stem ◽  
Ring Finger ◽  
Mouse Embryonic Stem Cells ◽  
Polycomb Group ◽  
Histone H2a ◽  
Cell Growth And Viability

The ring finger protein PCGF6 (polycomb group ring finger 6) interacts with RING1A/B and E2F6 associated factors to form a non-canonical PRC1 (polycomb repressive complex 1) known as PCGF6-PRC1. Here, we demonstrate that PCGF6-PRC1 plays a role in repressing a subset of PRC1 target genes by recruiting RING1B and mediating downstream mono-ubiquitination of histone H2A. PCGF6-PRC1 bound loci are highly enriched for promoters of germ cell-related genes in mouse embryonic stem cells (ESCs). Conditional ablation of Pcgf6 in ESCs leads to robust de-repression of such germ cell-related genes, in turn affecting cell growth and viability. We also find a role for PCGF6 in pre- and peri-implantation mouse embryonic development. We further show that a heterodimer of the transcription factors MAX and MGA recruits PCGF6 to target loci. PCGF6 thus links sequence specific target recognition by the MAX/MGA complex to PRC1-dependent transcriptional silencing of germ cell-specific genes in pluripotent stem cells.

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