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RYBP coordinates with Trithorax complex and selectively recruits Polycomb complex for cell fate control

ABSTRACT: The selective expression is pivotal in orchestrating human development, with the Trithorax Group (TrxG) and Polycomb Group (PcG) complexes playing crucial roles in transcriptional activation and repression, respectively. However, mechanism underlying selective regulation of transcription by TrxG and PcG remains poorly understood. In this study, RYBP was observed to interact with TrxG and PcG components. RYBP and TrxG co-localized loci selectively enriches RING1B. STAT3 enriches at RYBP-TrxG co-localized loci devoid of RING1B, while displaying minimal enrichment at RING1B-enrichred loci. Introduction of STAT3 at RYBP loci disrupted RING1B aggregation and chromatin binding. RYBP-deficiency impairs TrxG deposition at DNA repair genes in RYBP-TrxG loci, consequently diminishing their expression and inducing DNA damage. These results facilitate the transition of embryonic stem cells to 2-cell-like cells. Additionally, RYBP-deficiency attenuates PcG deposition at lineage-specific genes within RYBP-TrxG-RING1B loci, thereby promoting ESC differentiation. Collectively, these results provide novel insights into the selective regulation of gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE261485 | GEO | 2024/04/26

REPOSITORIES: GEO

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Functional dissection of PRC1 subunits RYBP and YAF2 during neural differentiation of embryonic stem cells

Project description:Polycomb repressive complex 1 (PRC1) comprises two different complexes: CBX-containing canonical PRC1 (cPRC1) and RYBP/YAF2-containing variant PRC1 (vPRC1). RYBP and its paralog YAF2 recruit vPRC1 to catalyze H2AK119ub through a positive-feedback model. Here, we show that expression of RYBP and YAF2 decreases and increases, respectively, during neural differentiation of embryonic stem cells (ESCs). Rybp knockout impairs neural differentiation by activating Wnt signaling and derepressing nonneuroectoderm-associated genes. However, Yaf2 knockout promotes neural differentiation and leads to redistribution of RYBP binding, increases enrichment of RYBP and H2AK119ub on the RYBP-YAF2 co-targeted genes, and prevents ectopic derepression of nonneuroectoderm-associated genes in neural-differentiated cells. Furthermore, the phase separations mediated by RYBP alone or together with RING1B are easier and more stable than those by YAF2, which might facilitate the deposition of H2AK119ub more abundantly by RYBP-PRC1 than YAF2-PRC1. Together, this study reveals that RYBP might maintain repressed chromatin more strongly and function differentially in regulating mESC neural differentiation compared with YAF2.

2023-10-09 | GSE213413 | GEO

A Polycomb Repressive Complex 1 proteome from Drosophila cells

Project description:Polycomb Group (PcG) proteins regulate gene expression through changes to chromatin structure and are essential for development. PcG proteins function together with the Trithorax Group (TrxG) proteins, which affect diverse steps in transcription activation. The PcG and TrxG are genetically and functionally antagonistic, and current understanding suggests a balance of their activities can maintain a wide range of transcription states. PcG and TrxG proteins assemble into a series of complexes. How these complexes work together, how PcG complexes are recruited to target genes, and whether other proteins are involved in their regulation of gene expression remain open questions. We carried out tandem affinity purification followed by mass spectrometry (TAP-MS) on two core components of Drosophila Polycomb Repressive Complex 1 (PRC1). Our data reveal a network of interactions among PcG complexes, and extensive co-purification of TrxG complexes with PRC1. We co-purified >50 transcription factors with PRC1 that were not previously linked to the PcG. Finally, we identify novel co-purifying complexes, including HP1c and PCNA handling complexes. Our resource of candidate PRC1 interacting proteins generate new hypotheses for PRC1 function.

2023-04-20 | MSV000091759 | MassIVE

The PRC1 protein RING1B contributes to Ewing sarcoma tumorigenesis by repressing the NaV1.6 sodium channel and modulating the NF-kB pathway, independently of the fusion oncoprotein.

Project description:Ewing sarcoma (ES) is an aggressive tumor molecularly defined by reciprocal translocations of EWSR1 to an ETS transcription factor. The functions of EZH2 and BMI1, two proteins of the Polycomb group (PcG) of epigenetic repressors, have been previously shown to mediate specific features in EWSR1/ETS-transformed cells. Here we have characterized the expression and function of RING1B, a PcG protein with unique abilities, in ES. RING1B is highly and universally expressed in primary ES tumors. In contrast to EZH2, RING1B expression is independent of both the oncogene and of differentiation agents. RING1B depletion affects heme biosynthesis and hematopoiesis but does not result in a widespread alteration in ES differentiation. Among the unique set of genes regulated upon RING1B depletion, FGF14 and SCN8A, interacting components of the NaV1.6 channel, are two of the most up-regulated genes. Control of FGF14 and SCN8A in ES is specific of RING1B and functionally relevant. The signaling pathway most significantly modulated by RING1B is NF-κB. Indeed, RING1B depletion results in enhanced p105/p50 expression, which specifically sensitizes ES cells to apoptosis by FGFR/SHP2/STAT3 blockade. In conclusion, we show that RING1B is pivotal in ES cells, independently of the fusion oncogene, likely reflecting essential functional traits of the cell-of-origin.

2016-06-30 | GSE71007 | GEO

An essential role for PTIP in mediating Hox gene regulation along PcG and trxG pathways

Project description:During Drosophila development, Polycomb-group and Trithorax-group proteins function to ensure correct maintenance of transcription patterns by epigenetically repressing or activating target gene expression. To get a deep insight into the PcG and trxG pathways, we investigated a BRCT domain-containing protein called PTIP, which was generally identified as a transcriptional coactivator and belongs to the TRR complex. At the genome scale, we sorted given PTIP binding peaks into two groups: PTIP/TRR-cobound and PTIP/PC-cobound peaks. In particular, we found that PTIP mediates the molecular switch between H3K4me3/H3K27ac and H3K27me3 histone modifications at TRR or PC occupied regions. Thus, we suggest that PTIP is a mediator rather than a dedicated co-activator along PcG and trxG pathways. Our hypothesis is further supported by the genetic assay: PTIP interacts genetically with either PcG or TrxG in a dosage-dependent manner, suggesting that PTIP functions as a co-factor of PcG/TrxG proteins. In addition, in accordance with the analysis of ChIP-seq, these genetic interactions correlate with modified ectopic HOX protein levels in imaginal discs, which reveals an essential role for PTIP in PcG-mediated Hox gene repression. Hence, we reveal a novel role for PTIP in the epigenetic regulation of gene expression along PcG and trxG pathways.

2022-05-23 | GSE203601 | GEO

Expression regulation by RYBP in mouse embryonic stem cells

Project description:Polycomb repressive complexes (PRCs) are important chromatin regulators of ES cell function. RYBP binds Polycomb H2A monoubiquitin ligases Ring1A and Ring1B, and has been suggested to participate in localizing Polycomb complexes to their targets. Moreover, constitutive inactivation of RYBP precludes ES cell formation. Here we have used ES cells conditionally deficient in RYBP to investigate RYBP function. Chromosome immunoprecipitation on a chip (ChIP-chip) of RYBP and microarray experiments were performed using wild type and knocked-out ES cells. Gene expression profiling of WT, conditionally deficient in RYBP with or without Yaf2 RNAi, and ChIP-chip of RYBP on promoters of WT, Dnmt1-KO or Eed-KO ES cells.

2012-04-03 | E-GEOD-32294 | biostudies-arrayexpress

The PRC1 protein RING1B contributes to Ewing sarcoma tumorigenesis by repressing the NaV1.6 sodium channel and modulating the NF-kB pathway, independently of the fusion oncoprotein.

Project description:Ewing sarcoma (ES) is an aggressive tumor molecularly defined by reciprocal translocations of EWSR1 to an ETS transcription factor. The functions of EZH2 and BMI1, two proteins of the Polycomb group (PcG) of epigenetic repressors, have been previously shown to mediate specific features in EWSR1/ETS-transformed cells. Here we have characterized the expression and function of RING1B, a PcG protein with unique abilities, in ES. RING1B is highly and universally expressed in primary ES tumors. In contrast to EZH2, RING1B expression is independent of both the oncogene and of differentiation agents. RING1B depletion affects heme biosynthesis and hematopoiesis but does not result in a widespread alteration in ES differentiation. Among the unique set of genes regulated upon RING1B depletion, FGF14 and SCN8A, interacting components of the NaV1.6 channel, are two of the most up-regulated genes. Control of FGF14 and SCN8A in ES is specific of RING1B and functionally relevant. The signaling pathway most significantly modulated by RING1B is NF-ÎºB. Indeed, RING1B depletion results in enhanced p105/p50 expression, which specifically sensitizes ES cells to apoptosis by FGFR/SHP2/STAT3 blockade. In conclusion, we show that RING1B is pivotal in ES cells, independently of the fusion oncogene, likely reflecting essential functional traits of the cell-of-origin. 10 samples were analyzed: A4573 transduced with control shRNA; A4573 transduced with shRING1B; A673 transduced with control shRNA; A673 transduced with shRING1B; SK-ES-1 transduced with control shRNA; SK-ES-1 transduced with shRING1B; TC71 transduced with control shRNA; TC71 transduced with shRING1B; A673 transduced with shBMI1; TC71 transduced with shBMI1

2016-06-30 | E-GEOD-71007 | biostudies-arrayexpress

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

Project description: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. 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.

2021-01-29 | GSE165685 | GEO

Polycomb preferentially targets stalled promoters of coding and non-coding transcripts

Project description:The Polycomb group (PcG) and Trithorax group (TrxG) of proteins are required for stable and heritable maintenance of repressed and active gene expression states. Their antagonistic function on gene control, repression for PcG and activity for TrxG, is mediated by binding to chromatin and subsequent epigenetic modification of target loci. Despite our broad knowledge about composition and enzymatic activities of the protein complexes involved, our understanding still lacks important mechanistic detail and a comprehensive view on target genes. In this study, we use an extensive data set of ChIP-seq, RNA-seq, and genome-wide detection of transcription start sites (TSSs) to identify and analyze thousands of binding sites for the PcG proteins and Trithorax from a Drosophila S2 cell line. In addition to finding a preference for stalled promoter regions of annotated genes, we uncover many intergenic PcG-binding sites coinciding with non-annotated transcription start sites. Interestingly, this set includes previously unknown promoters for primary transcripts of microRNA genes, thereby expanding the scope of Polycomb control to non-coding RNAs essential for development, apoptosis and growth.

2010-12-21 | GSE24521 | GEO

PcG/TrxG profiling of differentially aged adipose-derived mesenchymal stem cells

Project description:The microarray reported here is part of a study aimed to investigate whether the gene expression profile of Polycomb, Trithorax and interacting molecules (collectively referred to PcG/TrxG genes) might be related to different states of differentiative potential. In particular , this microarray profiles the expression of PcG/TrxG genes in adipose-derived mesenchymal stem cells isolated from the inguinal fat depot of mice of different age.

2010-11-30 | GSE25068 | GEO

Expression regulation by RYBP in mouse embryonic stem cells

Project description:Polycomb repressive complexes (PRCs) are important chromatin regulators of ES cell function. RYBP binds Polycomb H2A monoubiquitin ligases Ring1A and Ring1B, and has been suggested to participate in localizing Polycomb complexes to their targets. Moreover, constitutive inactivation of RYBP precludes ES cell formation. Here we have used ES cells conditionally deficient in RYBP to investigate RYBP function. Chromosome immunoprecipitation on a chip (ChIP-chip) of RYBP and microarray experiments were performed using wild type and knocked-out ES cells. This SuperSeries is composed of the SubSeries listed below.

2012-04-04 | GSE32294 | GEO

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