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Evolutionarily ancient BAH-PHD protein mediates Polycomb silencing.

ABSTRACT: Methylation of histone H3 lysine 27 (H3K27) is widely recognized as a transcriptionally repressive chromatin modification but the mechanism of repression remains unclear. We devised and implemented a forward genetic scheme to identify factors required for H3K27 methylation-mediated silencing in the filamentous fungus Neurospora crassa and identified a bromo-adjacent homology (BAH)-plant homeodomain (PHD)-containing protein, EPR-1 (effector of polycomb repression 1; NCU07505). EPR-1 associates with H3K27-methylated chromatin, and loss of EPR-1 de-represses H3K27-methylated genes without loss of H3K27 methylation. EPR-1 is not fungal-specific; orthologs of EPR-1 are present in a diverse array of eukaryotic lineages, suggesting an ancestral EPR-1 was a component of a primitive Polycomb repression pathway.

SUBMITTER: Wiles ET

PROVIDER: S-EPMC7261115 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Evolutionarily ancient BAH-PHD protein mediates Polycomb silencing.

Wiles Elizabeth T ET McNaught Kevin J KJ Kaur Gurmeet G Selker Jeanne M L JML Ormsby Tereza T Aravind L L Selker Eric U EU

Proceedings of the National Academy of Sciences of the United States of America 20200511 21

Methylation of histone H3 lysine 27 (H3K27) is widely recognized as a transcriptionally repressive chromatin modification but the mechanism of repression remains unclear. We devised and implemented a forward genetic scheme to identify factors required for H3K27 methylation-mediated silencing in the filamentous fungus <i>Neurospora crassa</i> and identified a bromo-adjacent homology (BAH)-plant homeodomain (PHD)-containing protein, EPR-1 (effector of polycomb repression 1; NCU07505). EPR-1 associ ...[more]

PMID: 32393638

Similar Datasets

Evolutionarily ancient BAH-PHD protein mediates Polycomb silencing in Neurospora crassa

Project description:Here we utilize a forward genetics approach in Neurospora crassa to identify novel effectors of Polycomb repression. We recovered several mutant alleles of a gene (NCU07505),which we deemed effector of Polycomb repression 1 (epr-1), encoding a protein with a bromo-adjacent homology (BAH) domain and plant homeodomain (PHD) finger. Although epr-1mutants display phenotypic and gene expression changes similar to strains lacking PRC2 components, H3K27 methylation is notably unaffected. We demonstrate that EPR-1 forms nuclear foci, reminiscent of Polycomb bodies {Pirrotta:2012br}, and its genomic distribution is limited to and dependent upon H3K27-methylated chromatin, which it recognizes through its BAH domain. Finally, we discover that EPR-1 homologs are widely distributed across eukaryotes, contrary to previous reports {LopezGonzalez:2014id, Li:2018kg}, suggesting an ancient role of EPR-1 homologs in Polycomb repression that was secondarily lost in select lineages.

2020-04-15 | GSE128317 | GEO

Evolutionarily ancient BAH-PHD protein mediates Polycomb silencing in Neurospora crassa

Project description:Evolutionarily ancient BAH-PHD protein mediates Polycomb silencing in Neurospora crassa

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A conserved BAH module within mammalian BAHD1 connects H3K27me3 to Polycomb gene silencing.

Project description:Trimethylation of histone H3 lysine 27 (H3K27me3) is important for gene silencing and imprinting, (epi)genome organization and organismal development. In a prevalent model, the functional readout of H3K27me3 in mammalian cells is achieved through the H3K27me3-recognizing chromodomain harbored within the chromobox (CBX) component of canonical Polycomb repressive complex 1 (cPRC1), which induces chromatin compaction and gene repression. Here, we report that binding of H3K27me3 by a Bromo Adjacent Homology (BAH) domain harbored within BAH domain-containing protein 1 (BAHD1) is required for overall BAHD1 targeting to chromatin and for optimal repression of the H3K27me3-demarcated genes in mammalian cells. Disruption of direct interaction between BAHD1BAH and H3K27me3 by point mutagenesis leads to chromatin remodeling, notably, increased histone acetylation, at its Polycomb gene targets. Mice carrying an H3K27me3-interaction-defective mutation of Bahd1BAH causes marked embryonic lethality, showing a requirement of this pathway for normal development. Altogether, this work demonstrates an H3K27me3-initiated signaling cascade that operates through a conserved BAH 'reader' module within BAHD1 in mammals.

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A repressive H3K36me2 reader mediates Polycomb silencing

Project description: Not available

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A PHD-polycomb repressive complex 2 triggers the epigenetic silencing of FLC during vernalization.

Project description:Vernalization, the acceleration of flowering by winter, involves cold-induced epigenetic silencing of Arabidopsis FLC. This process has been shown to require conserved Polycomb Repressive Complex 2 (PRC2) components including the Su(z)12 homologue, VRN2, and two plant homeodomain (PHD) finger proteins, VRN5 and VIN3. However, the sequence of events leading to FLC repression was unclear. Here we show that, contrary to expectations, VRN2 associates throughout the FLC locus independently of cold. The vernalization-induced silencing is triggered by the cold-dependent association of the PHD finger protein VRN5 to a specific domain in FLC intron 1, and this association is dependent on the cold-induced PHD protein VIN3. In plants returned to warm conditions, VRN5 distribution changes, and it associates more broadly over FLC, coincident with significant increases in H3K27me3. Biochemical purification of a VRN5 complex showed that during prolonged cold a PHD-PRC2 complex forms composed of core PRC2 components (VRN2, SWINGER [an E(Z) HMTase homologue], FIE [an ESC homologue], MSI1 [p55 homologue]), and three related PHD finger proteins, VRN5, VIN3, and VEL1. The PHD-PRC2 activity increases H3K27me3 throughout the locus to levels sufficient for stable silencing. Arabidopsis PHD-PRC2 thus seems to act similarly to Pcl-PRC2 of Drosophila and PHF1-PRC2 of mammals. These data show FLC silencing involves changed composition and dynamic redistribution of Polycomb complexes at different stages of the vernalization process, a mechanism with greater parallels to Polycomb silencing of certain mammalian loci than the classic Drosophila Polycomb targets.

| S-EPMC2579339 | biostudies-literature

Ikaros mediates gene silencing in T cells through Polycomb repressive complex 2.

Project description:T-cell development is accompanied by epigenetic changes that ensure the silencing of stem cell-related genes and the activation of lymphocyte-specific programmes. How transcription factors influence these changes remains unclear. We show that the Ikaros transcription factor forms a complex with Polycomb repressive complex 2 (PRC2) in CD4(-)CD8(-) thymocytes and allows its binding to more than 500 developmentally regulated loci, including those normally activated in haematopoietic stem cells and others induced by the Notch pathway. Loss of Ikaros in CD4(-)CD8(-) cells leads to reduced histone H3 lysine 27 trimethylation and ectopic gene expression. Furthermore, Ikaros binding triggers PRC2 recruitment and Ikaros interacts with PRC2 independently of the nucleosome remodelling and deacetylation complex. Our results identify Ikaros as a fundamental regulator of PRC2 function in developing T cells.

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The polycomb group protein PCGF6 mediates germline gene silencing by recruiting histone-modifying proteins to target gene promoters.

Project description:Polycomb group (PcG) proteins are essential for maintenance of lineage fidelity by coordinating developmental gene expression programs. Polycomb group ring finger 6 (PCGF6) has been previously reported to repress expression of lineage-specific genes, especially germ cell-related genes in mouse embryonic stem cells (ESCs) via the noncanonical polycomb repressive complex PRC1.6. However, the molecular mechanism of this repression remains largely unknown. Here, using RNA-Seq, real-time RT-PCR, immunohistochemistry, immunoprecipitation, and ChIP analyses, we demonstrate that PCGF6 plays an essential role in embryonic development, indicated by the partially penetrant embryonic lethality in homozygous PCGF6 (Pcgf6 -/-)-deficient mice. We also found that surviving Pcgf6-deficient mice exhibit reduced fertility. Using the Pcgf6-deficient mice, we observed that ablation of Pcgf6 in somatic tissues robustly derepresses germ cell-related genes. We further provide evidence that these genes are direct targets of PCGF6 in ESCs and that endogenous PCGF6 co-localizes with the histone-modifying proteins G9A histone methyltransferase (G9A)/G9a-like protein (GLP) and histone deacetylase 1/2 (HDAC1/2) on the promoters of the germ cell-related genes. Moreover, the binding of these proteins to their target genes correlated with methylation of Lys-9 of histone 3 and with the status of histone acetylation at these genes. Moreover, the recruitment of G9A/GLP and HDAC1/2 to target promoters depended on the binding of PCGF6. Our findings indicate that PCGF6 has a critical role in safeguarding lineage decisions and in preventing aberrant expression of germ cell-related genes.

| S-EPMC7363147 | biostudies-literature

Abscisic acid negatively regulates the Polycomb-mediated H3K27me3 through the PHD-finger protein, VIL1.

Project description:Polycomb dictates developmental programs in higher eukaryotes, including flowering plants. A phytohormone, abscisic acid (ABA), plays a pivotal role in seed and seedling development and mediates responses to multiple environmental stresses, such as salinity and drought. In this study, we show that ABA affects the Polycomb Repressive Complex 2 (PRC2)-mediated Histone H3 Lys 27 trimethylation (H3K27me3) through VIN3-LIKE1/VERNALIZATION 5 (VIL1/VRN5) to fine-tune the timely repression of ABSCISIC ACID INSENSITIVE 3 (ABI3) and ABSCISIC ACID INSENSITIVE 4 (ABI4) in Arabidopsis thaliana. vil1 mutants exhibit hypersensitivity to ABA during early seed germination and show enhanced drought tolerance. Our study revealed that the ABA signaling pathway utilizes a facultative component of the chromatin remodeling complex to demarcate the level of expression of ABA-responsive genes.

| S-EPMC9673473 | biostudies-literature

Coupling of H3K27me3 recognition with transcriptional repression through the BAH-PHD-CPL2 complex in Arabidopsis.

Project description:Histone 3 Lys 27 trimethylation (H3K27me3)-mediated epigenetic silencing plays a critical role in multiple biological processes. However, the H3K27me3 recognition and transcriptional repression mechanisms are only partially understood. Here, we report a mechanism for H3K27me3 recognition and transcriptional repression. Our structural and biochemical data showed that the BAH domain protein AIPP3 and the PHD proteins AIPP2 and PAIPP2 cooperate to read H3K27me3 and unmodified H3K4 histone marks, respectively, in Arabidopsis. The BAH-PHD bivalent histone reader complex silences a substantial subset of H3K27me3-enriched loci, including a number of development and stress response-related genes such as the RNA silencing effector gene ARGONAUTE 5 (AGO5). We found that the BAH-PHD module associates with CPL2, a plant-specific Pol II carboxyl terminal domain (CTD) phosphatase, to form the BAH-PHD-CPL2 complex (BPC) for transcriptional repression. The BPC complex represses transcription through CPL2-mediated CTD dephosphorylation, thereby causing inhibition of Pol II release from the transcriptional start site. Our work reveals a mechanism coupling H3K27me3 recognition with transcriptional repression through the alteration of Pol II phosphorylation states, thereby contributing to our understanding of the mechanism of H3K27me3-dependent silencing.

| S-EPMC7718874 | biostudies-literature

A conserved BAH module within mammalian BAHD1 connects H3K27me3 to Polycomb gene silencing

Project description:Trimethylation of histone H3 lysine 27 (H3K27me3) is important for gene silencing, (epi)genome organization and organismal development. In a prevalent model, the functional “readout” of H3K27me3 in mammalian cells is achieved through the H3K27me3-recognizing chromodomain harbored within the chromobox (CBX) component of canonical Polycomb repressive complex 1 (cPRC1), which induces chromatin compaction and gene repression. Here, we report that binding of H3K27me3 by a Bromo Adjacent Homology (BAH) domain harbored within BAH domain-containing protein 1 (BAHD1) is required for overall BAHD1 targeting to chromatin and for optimal repression of the H3K27me3-demarcated genes in mammalian cells. Disruption of direct interaction between BAHD1-BAH and H3K27me3 by point mutagenesis leads to chromatin remodeling, notably, increased histone acetylation, at its Polycomb gene targets. Mice carrying an H3K27me3-interaction-defective mutation of Bahd1BAH causes marked embryonic lethality, showing a requirement of this pathway for normal development. Altogether, this work demonstrates an H3K27me3-initiated signaling cascade that operates through a conserved BAH “reader” module within BAHD1 in mammals.

2021-03-16 | GSE167079 | GEO

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