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DNMTs and SETDB1 function as co-repressors in MAX-mediated repression of germ cell-related genes in mouse embryonic stem cells

ABSTRACT: In embryonic stem cells (ESCs), the expression of development-related genes, including germ cell-related genes, is globally repressed. The transcription factor MAX represses germ cell-related gene expression in ESCs via PCGF6-polycomb repressive complex (PRC)1, which consists of several epigenetic factors. However, we predicted that MAX represses germ cell-related gene expression through several additional mechanisms because PCGF6-PRC1 regulates the expression of only a subset of genes repressed by MAX. Here, we report that MAX associated with DNA methyltransferases (DNMTs) and the histone methyltransferase SETDB1 cooperatively control germ cell-related gene expression in ESCs. Both DNA methylation and histone H3 lysine 9 tri-methylation of the promoter regions of several germ cell-related genes were not affected by knockout of the PRC1 components, indicating that the MAX-DNMT and MAX-SETDB1 pathways are independent of the PCGF6-PRC1 pathway. Our findings provide insights into our understanding of MAX-based repressive mechanisms of germ cell-related genes in ESCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE102610 | GEO | 2018/08/31

REPOSITORIES: GEO

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Max is a repressor of germ-cell-related gene expression in mouse embryonic stem cells

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Project description:Polycomb group (PcG) proteins comprise a large group of evolutionary conserved factors with essential roles for embryonic development and adult stem cell function. PcG proteins constitute two main multiprotein polycomb repressive complexes (PRC1 and PRC2) that operate in a hierarchical manner to silence gene expression. Functionally distinct PRC1 complexes are defined by Polycomb group RING finger protein (PCGF) paralogs. So far, six PCGF paralogs (PCGF1-6) have been identified but paralog-specific functions are not well understood. In our studies, we observed that Pcgf6 showed the highest expression level in undifferentiated murine embryonic stem cells (ESCs), blastocysts and testes. When ESCs differentiated, Pcgf6 expression strongly declined. To further investigate Pcgf6 biology, we established dox-inducible shRNA knockdown (KD) ESCs. Following Pcgf6 KD in ESCs the expression of pluripotency genes decreased, while mesodermal- and spermatogenesis-specific genes were de-repressed. Concomitantly with the elevated expression of mesodermal lineage markers, Pcgf6 KD ESCs showed increased hemangioblastic and hematopoietic activities. Finally, PCGF6 replaced SOX2 but not KLF4 or c-MYC in the generation of germline-competent iPS cells. Forced expression of Pcgf6 in OSKM-driven reprogramming increases iPS efficiency while Pcgf6 KD reduces the formation of ESC-like colonies. Together, these analyses show that Pcgf6 is non-redundantly involved in maintaining the pluripotent nature of ESCs and functions in iPS reprogramming. 6 samples were hybridized GeneChip Mouse Gene 1.0 ST Arrays (Affymetrix)

2014-09-26 | E-GEOD-56126 | biostudies-arrayexpress

Max is a repressor of germ-cell-related gene expression in mouse embryonic stem cells

Project description:Embryonic stem cells (ESCs) and primordial germ cells (PGCs) express many pluripotency-associated genes, but ESCs do not normally undergo conversion into PGCs. Thus, we predicted that there is a mechanism that represses PGC-related gene expression in ESCs. Here we identify genes involved in this putative mechanism, by using an ESC line with a Vasa reporter for an RNAi screen of transcription factor genes expressed in ESCs. We identify 5 genes that result in the expression of Vasa when silenced. Of these, Max is the most striking. Transcriptome analysis reveals that Max knockdown (KD) in ESCs results in selective, global derepression of germ-cell-specific genes. Max interacts with histone H3K9 methyltransferases and associates with the germ-cell-specific genes in ESCs. In addition, Max-KD results in a decrease in histone H3K9 dimethylation at their promoter regions. We propose that Max is part of a protein complex that acts as a repressor of germ-cell-related genes in ESCs. Gene expression profile of Vasa-positive cells isolated from Max knockdown ESCs was compared to that of normal ESCs and in vivo PGCs. As an ESCs sample, a mouse embryonic stem cell line that carries a Venus reporter driven by the Vasa gene promoter (VV3) was used for this study. VV3 ESCs were transfected with non-silencing negative control siRNA (AllStars) or siRNA against the Max gene. Vasa-positive cells were purified using fluorescence-activated cell sorting (FACS). As a PGCs sample, a mouse strain that carries a germ-cell-specific GFP reporter (Oct4M-NM-^TPE-GFP) was used. PGCs were also purified using FACS. RNA samples were isolated from each sample and labeled and hybridized to Agilent microarrays. Three biological replicates were performed for each group of samples.

2013-05-01 | E-GEOD-45181 | biostudies-arrayexpress

Polycomb Group Protein Pcgf6 Acts as a Master Regulator to Maintain Embryonic Stem Cell Identity

Project description:We report that the PRC1 component polycomb group ring finger 6 (Pcgf6) is required to maintain embryonic stem cell (ESC) identity. In contrast to canonical PRC1, Pcgf6 acts as a positive regulator of transcription and binds predominantly to promoters bearing active chromatin marks. Pcgf6 is expressed at high levels in ESCs, and knockdown reduces the expression of the core ESC regulators Oct4,Sox2, and Nanog. Conversely, Pcgf6 overexpression prevents downregulation of these factors and impairs differentiation. In addition, Pcgf6 enhanced reprogramming in both mouse and human somatic cells. The genomic binding profile of Pcgf6 is highly similar to that of trithorax group proteins, but not of PRC1 or PRC2 complexes, suggesting that Pcgf6 functions atypically in ESCs. Our data reveal novel roles for Pcgf6 in directly regulating Oct4, Nanog, Sox2, and Lin28 expression to maintain ESC identity.

2016-07-28 | GSE84905 | GEO

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Project description:MAX (MYC Associated Factor X) is generally known as a mandatory partner for MYC transcription factor, which activates various genes involved in cell growth and metabolism. On the other hand, MAX, when interacting with MGA, forms the polycomb repressive complex (PRC) 1.6, one of the subtypes of PRC1, which directs the transcriptionally repressed chromatin state. Although physiological significance is not known at present, we have previously demonstrated that mouse embryonic stem cells (ESCs) bear a potential to onset meiosis, albeit not germ cells, and PRC1.6 prevent ESCs from their ectopic onset of meiosis (Suzuki et al., 2016, Nat. Commun. 7:11056 doi: 10.1038/ncomms11056). In this study, we aimed to investigate the role of Max in germ cells in vivo by performing the primordial germ cell-specific knockout of the Max gene.

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2019-04-29 | GSE122715 | GEO

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