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Auto-inhibition of PRC2 by the broadly expressed long isoform of AEBP2.

ABSTRACT: Polycomb Repressive Complex 2 (PRC2) is an essential chromatin regulator responsible for mono-, di- and tri- methylating H3K27. Control of PRC2 activity is a critical process in development and disease. While PRC2 is inhibited in germinal cells, no inhibitory cofactor has been identified in somatic cells. Here we show that the alternative isoforms of its accessory subunit AEBP2, namely AEBP2 S (short) and AEBP2L (long), perform opposite functions in modulating PRC2 activity. While AEBP2S is predominantly expressed during early embryogenesis, AEBP2L is expressed throughout embryogenesis and adulthood. AEBP2L inhibits both DNA binding by PRC2 and its histone methyltransferase activity in vitro and impairs PRC2 binding to target genes in embryonic stem cells. In contrast, AEBP2S promotes the DNA-binding activity of PRC2 and is essential for de novo repression of target genes during the transition from naïve to primed pluripotency. Mechanistically, through high-resolution Cryo-EM and mutagenesis, we show that the recently evolved, negatively charged N-terminal region of AEBP2L inhibits PRC2. We propose a model in which the N-terminus of AEBP2L arose in vertebrates to restrain PRC2 activity in somatic cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE217538 | GEO | 2025/09/16

REPOSITORIES: GEO

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Auto-inhibition of PRC2 by the broadly expressed long isoform of AEBP2.

Project description:Polycomb Repressive Complex 2 (PRC2) is an essential chromatin regulator responsible for mono-, di- and tri- methylating H3K27. Control of PRC2 activity is a critical process in development and disease. While PRC2 is inhibited in germinal cells, no inhibitory cofactor has been identified in somatic cells. Here we show that the alternative isoforms of its accessory subunit AEBP2, namely AEPB2S (short) and AEBP2L (long), perform opposite functions in modulating PRC2 activity. While AEPB2S is predominantly expressed during early embryogenesis, AEBP2L is expressed throughout embryogenesis and adulthood. AEPB2L inhibits both DNA binding by PRC2 and its histone methyltransferase activity in vitro and impairs PRC2 binding to target genes in embryonic stem cells. In contrast, AEBP2S promotes the DNA-binding activity of PRC2 and is essential for de novo repression of target genes during the transition from naïve to primed pluripotency. Mechanistically, through high-resolution Cryo-EM and mutagenesis, we show that the recently evolved, negatively charged N-terminal region of AEBP2L inhibits PRC2. We propose a model in which the N-terminus of AEPB2L arose in vertebrates to restrain PRC2 in somatic cells.

2025-08-26 | PXD053693 | Pride

Functional analysis of AEBP2, a PRC2 Polycomb protein, reveals a Trithorax phenotype in embryonic development and in ES cells

Project description:The Polycomb repressive complexes PRC1 and PRC2 are key mediators of heritable gene silencing in multicellular organisms. Here we characterize AEBP2, a known PRC2 cofactor which, in vitro, has been shown to stimulate PRC2 activity. We show that AEBP2 localises specifically to PRC2 target loci, including the inactive X chromosome. Proteomic analysis confirms that AEBP2 associates exclusively with PRC2 complexes. However, analysis of embryos homozygous for a targeted mutation of Aebp2 unexpectedly revealed a Trithorax phenotype, normally linked to antagonism of Polycomb function. Consistent with this we observe elevated levels of PRC2 mediated histone H3K27 methylation at target loci in Aebp2 mutant embryonic stem cells. We further demonstrate that mutant ES cells assemble atypical hybrid PRC2 sub-complexes, potentially accounting for enhancement of Polycomb activity, and suggesting that AEBP2 normally plays a role in defining the mutually exclusive composition of PRC2 sub-complexes. H3K27me3, SUZ12, and AEBP2 ChIP-Seq in wild-type and AEBP2 KO mouse ESCs, biological replicates, pre-cleared chromatin as input, additionally FS2 ChIP-Seq in cells with FS2 tagged AEBP2, HiSeq2000

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AEBP2’s roles in cell migration and Polycomb Repressive Complex 2 (PRC2)

Project description:Aebp2 encodes a zinc finger protein that is associated with the Polycomb Repressive Complex 2 (PRC2). The alternative promoters and protein isoforms of Aebp2 have been characterized in this study. Aebp2 is controlled through three alternative promoters, deriving three different transcripts which encode the embryonic (32 kDa) and somatic (52 kDa) forms. Chromatin ImmunoPrecipitation (ChIP) experiments revealed that AEBP2 binds to its own promoter as well as the promoters of Jarid2 and Snai2. While the embryonic form acts as a transcriptional repressor for Snai2, the somatic form functions as a transcriptional activator for Jarid2, Aebp2 and Snai2. Cell migration assays suggest that the Aebp2 somatic form can enhance cell migration. This is consistent with the functional association of Aebp2 with migratory neural crest cells. Overall, the two protein isoforms of AEBP2 may have opposite functions for the PcG target genes, and may play significant roles in cell migration during development.

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The transcriptional repressor AEBP2 is indispensable for the epigenetic control of mimetic thymic epithelial cell differentiation and central self-tolerance induction.

Project description:Polycomb repressive complex 2 (PRC2) plays a critical role in gene silencing by catalyzing the addition of H3K27me3 marks to chromatin, a modification essential for maintaining developmental gene repression. In thymic epithelial cells (TECs), PRC2 is required for the differentiation and function of medullary TECs (mTECs) but not cortical TECs. This study investigates the role of AEBP2, an accessory subunit of PRC2, in TEC biology, focusing on its impact on thymus development and central tolerance. We demonstrate that AEBP2 is crucial for the maintenance and differentiation of specific TEC subtypes, including microfold TEC, endoTEC, and Tuft cells. Loss of AEBP2 in TECs results in increased thymic cellularity but impairs the expression of tissue-restricted antigens (TRAs) critical for negative selection of thymocytes. The absence of AEBP2 leads to altered chromatin modifications, with changes in H3K27me3 marks at certain specific TRAs’ loci, suggesting a role in the epigenetic regulation of TRA expression. Furthermore, the loss of AEBP2 correlates with a greater risk of autoimmunity, as evidenced by increased T and B lymphocyte infiltration in peripheral organs. These findings highlight the essential role of AEBP2 in regulating TEC differentiation and self-antigen presentation, providing new insights into the molecular mechanisms of central T cell tolerance.

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A New Family of Vertebrate Specific Polycomb Proteins Encoded by the LCOR and LCORL Gene Loci Reveal Antagonism Between PRC2 Subtypes

Project description:The Polycomb Repressive Complex 2 (PRC2) is composed of core subunits SUZ12, EED, RBBP4/7 and EZH1/2, which together are responsible for all di- and tri- methylation of lysine 27 on Histone H3 (H3K27me2/3) in higher eukaryotes. While two distinct forms, PRC2.1 (containing one Polycomb-like protein) and PRC2.2 (containing AEBP2 and JARID2) exist, little is known about their differential functions or interplay. Here we report the discovery of a new family of vertebrate specific PRC2.1 associated proteins; ‘PRC2 associated LCOR isoform 1’ (PALI1) and PALI2, encoded by the LCOR and LCORL gene loci, respectively. PALI1 promotes PRC2 methyltransferase activity in vitro and in vivo and is essential for mouse development. We uncover an antagonistic relationship between the PALI-PRC2.1 and AEBP2-PRC2.2 subtypes and establish that both are required for balanced regulation of Polycomb target genes during differentiation. This discovery links the Polycomb epigenetic system with co-repressors and nuclear receptors in the regulation of cellular identity.

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Arabidopsis thaliana

Project description:embryogenesis ws-somatic embryogenesis

| PRJNA143431 | ENA

Arabidopsis thaliana

Project description:embryogenesis col0-somatic embryogenesis

| PRJNA143393 | ENA

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