Polycomb regulation is coupled to cell cycle transition in pluripotent stem cells

Asenjo, Helena G; Gallardo, Amador; López-Onieva, Lourdes; Tejada, Irene; Martorell-Marugán, Jordi; Carmona-Sáez, Pedro; Landeira, David

doi:10.1126/sciadv.aay4768

Cited by 38 publications

(19 citation statements)

References 51 publications

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“…Besides, DNA maintenance methyltransferase (DNMT1) and the proteins that reverse DNA methylation, i.e., Tet1 and Tet2, are also phosphorylated by CDK1 ( Michowski et al, 2020 ). Additionally, the identification of cell cycle regulators in our screen ( Figure 1B and Supplementary Table 1 ) supports the notion that PcG/trxG system is regulated in a cell cycle dependent manner ( Laprell et al, 2017 ; Asenjo et al, 2020 ), which may play a role in faithful inheritance of epigenetic states across cell divisions.…”

Section: Discussionsupporting

confidence: 80%

Kinome-Wide RNAi Screen Uncovers Role of Ballchen in Maintenance of Gene Activation by Trithorax Group in Drosophila

Khan

Akhtar

Umer

et al. 2021

Front. Cell Dev. Biol.

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Polycomb group (PcG) and trithorax group (trxG) proteins are evolutionary conserved factors that contribute to cell fate determination and maintenance of cellular identities during development of multicellular organisms. The PcG maintains heritable patterns of gene silencing while trxG acts as anti-silencing factors by conserving activation of cell type specific genes. Genetic and molecular analysis has revealed extensive details about how different PcG and trxG complexes antagonize each other to maintain cell fates, however, the cellular signaling components that contribute to the preservation of gene expression by PcG/trxG remain elusive. Here, we report an ex vivo kinome-wide RNAi screen in Drosophila aimed at identifying cell signaling genes that facilitate trxG in counteracting PcG mediated repression. From the list of trxG candidates, Ballchen (BALL), a histone kinase known to phosphorylate histone H2A at threonine 119 (H2AT119p), was characterized as a trxG regulator. The ball mutant exhibits strong genetic interactions with Polycomb (Pc) and trithorax (trx) mutants and loss of BALL affects expression of trxG target genes. BALL co-localizes with Trithorax on chromatin and depletion of BALL results in increased H2AK118 ubiquitination, a histone mark central to PcG mediated gene silencing. Moreover, BALL was found to substantially associate with known TRX binding sites across the genome. Genome wide distribution of BALL also overlaps with H3K4me3 and H3K27ac at actively transcribed genes. We propose that BALL mediated signaling positively contributes to the maintenance of gene activation by trxG in counteracting the repressive effect of PcG.

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Section: Discussionsupporting

confidence: 80%

Kinome-Wide RNAi Screen Uncovers Role of Ballchen in Maintenance of Gene Activation by Trithorax Group in Drosophila

Khan

Akhtar

Umer

et al. 2021

Front. Cell Dev. Biol.

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“…In addition to the ability of CBX and PHC subunits of canonical PRC1 to engage in high-order chromatin structure [ 42 , 43 , 44 , 45 ], other important activities are contributed by accessory subunits. For example, binding to DNA KDM2B, MGA-MAX, or E2F6-DPA in PRC1 [ 46 , 47 , 48 , 49 ], PCL homologs, JARID2 or AEBP2 in PRC2 [ 50 , 51 , 52 , 53 , 54 ], or specific recognition of histone tails (CBX subunits in PRC1 or EED and RBBP4,7 in PRC2 [ 36 , 55 , 56 ]. The pool of Polycomb complexes displayed in each cell type is determined by the expression levels of each of the subunits, an aspect of the system still poorly characterized.…”

Section: The Polycomb Systemmentioning

confidence: 99%

Functions of Polycomb Proteins on Active Targets

Giner-Laguarda

Vidal

2020

Epigenomes

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Chromatin regulators of the Polycomb group of genes are well-known by their activities as transcriptional repressors. Characteristically, their presence at genomic sites occurs with specific histone modifications and sometimes high-order chromatin structures correlated with silencing of genes involved in cell differentiation. However, evidence gathered in recent years, on flies and mammals, shows that in addition to these sites, Polycomb products bind to a large number of active regulatory regions. Occupied sites include promoters and also intergenic regions, containing enhancers and super-enhancers. Contrasting with occupancies at repressed targets, characteristic histone modifications are low or undetectable. Functions on active targets are dual, restraining gene expression at some targets while promoting activity at others. Our aim here is to summarize the evidence available and discuss the convenience of broadening the scope of research to include Polycomb functions on active targets.

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“…Such an involvement of cell cycle regulators in maintenance of epigenetic cellular memory corroborates with the gradual decrease in PRC2 mediated H3K27me3 levels with each round of cell division in flies (Laprell et al, 2017). Similarly differential recruitment of PRC2 subunits to cell lineage-specific promoters is reported across cell cycle in mouse embryonic stem cells (mESCs) (Asenjo et al, 2020). Identification of cell cycle regulators in our screen supports the notion that PcG/trxG system is regulated in a cell cycle dependent manner (Laprell et al, 2017; Asenjo et al, 2020), which may play a role in faithful inheritance of epigenetic states.…”

Section: Discussionmentioning

confidence: 68%

Kinome-wide RNAi screen uncovers role of Ballchen in maintenance of gene activation by trithorax group in Drosophila

Khan

Akhtar

Umer

et al. 2020

Preprint

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Polycomb group (PcG) and trithorax group (trxG) proteins are evolutionary conserved factors that contribute to cell fate determination and maintenance of cellular identities during development of multicellular organisms. The PcG behaves as repressors to maintain heritable patterns of gene silencing and trxG act as anti-silencing factors by maintaining activation of cell type specific genes. Genetic and molecular analysis has revealed extensive details about how different PcG and trxG complexes antagonize each other to maintain cell fates, however the cellular signaling components that contribute to maintenance of gene expression by PcG/trxG remain elusive. Here, we report an ex vivo kinome-wide RNAi screen in Drosophila aimed to identify cell signaling genes that facilitate trxG to counteract PcG mediated repression. From the list of trxG candidates, Ballchen (BALL), a histone kinase, known to phosphorylate histone H2A at threonine 119 (H2AT119p), was characterized as a trxG regulator. The ball mutant exhibit strong genetic interaction with Polycomb (Pc) and trithorax (trx) mutants and loss of BALL also affects expressions of trxG target genes in ball mutant embryos. BALL co-localizes with Trithorax on chromatin and depletion of BALL results in increased H2AK118 ubiquitination, a histone mark central to PcG mediated gene silencing. Moreover, analysis of genome-wide binding profile of BALL shows an overlap with 85% known binding sites of TRX across the genome. Both BALL and TRX are highly enriched at actively transcribed genes, which also correlate with presence of H3K4me3 and H3K27ac. We propose that BALL mediated signal positively contributes to the maintenance of gene activation by trxG by counteracting the repressive effect of PcG.

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Polycomb regulation is coupled to cell cycle transition in pluripotent stem cells

Cited by 38 publications

References 51 publications

Kinome-Wide RNAi Screen Uncovers Role of Ballchen in Maintenance of Gene Activation by Trithorax Group in Drosophila

Kinome-Wide RNAi Screen Uncovers Role of Ballchen in Maintenance of Gene Activation by Trithorax Group in Drosophila

Functions of Polycomb Proteins on Active Targets

Kinome-wide RNAi screen uncovers role of Ballchen in maintenance of gene activation by trithorax group in Drosophila

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