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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE167079 | GEO | 2021/03/16

REPOSITORIES: GEO

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BAHD1 couples H3K27me3 to gene silencing via a conserved BAH reader module and associated corepressor complex in mammals (RNA-Seq)

Project description:Trimethylation of histone H3 lysine 27 (H3K27me3) is crucially involved for gene silencing, (epi)genome organization, cell-fate decision-making and development. To date, functional readout of H3K27me3 is viewed to be achieved mainly through a class of H3K27me3-recognizing chromodomains harbored within the chromobox (CBX) subunit of Polycomb repressive complex 1 (PRC1), which causes chromatin compaction and gene repression partly through histone H2A lysine 119 mono-ubiquitination. We here report that engagement of H3K27me3 by an evolutionarily conserved bromo adjacent homology (BAH) domain harbored within BAH domain-containing protein 1 (BAHD1) significantly contributes to optimal repression of the H3K27me3-demarcated genes in mammalian cells. BAHD1 assembles a NurD-like transcriptional corepressor complex. Abolishing the BAHD1BAH:H3K27me3 interaction by point mutagenesis interferes with BAHD1 binding to chromatin, leading to chromatin remodeling and derepression of Polycomb target genes. Mice carrying an H3K27me3-binding-defective mutation of Bahd1BAH causes marked embryonic lethality, indicating a requirement of this pathway for development. Altogether, this work demonstrates an H3K27me3-initiated signaling cascade that operates through a conserved BAH ‘reader’ module class in mammals.

2021-03-16 | GSE160058 | GEO

BAHD1 couples H3K27me3 to gene silencing via a conserved BAH reader module and associated corepressor complex in mammals (ChIP-Seq)

2021-03-16 | GSE160060 | GEO

BAHD1 couples H3K27me3 to gene silencing via a conserved BAH reader module and associated corepressor complex in mammals (CUT&RUN)

2021-03-16 | GSE160059 | GEO

Histone H3 Lys27 trimethylation readout by a BAH domain of BAHCC1 directs gene silencing [RNAseq_jurkat_O3SH2_RS4SH2]

Project description:The Polycomb Repressive Complex 2 (PRC2) and its trimethylation of histone H3 at lysine 27 (H3K27me3) control gene silencing, genome organization, cell-fate determination, as well as normal and pathological development. To date, functional transduction of H3K27me3 is believed to be achieved through the H3K27me3-‘recognizing’ chromodomain harbored within the chromobox (CBX) subunit of Polycomb Repressive Complex 1 (PRC1), which mediates gene silencing partly through H2A monoubiquitination. Here, we report a novel H3K27me3-readout mechanism in mammal, which utilizes an evolutionarily conserved Bromo-adjacent homology (BAH) domain of BAHCC1 (BAH domain and Coiled-Coil Containing 1) for silencing polycomb gene targets. Biochemical, structural and chromatin-immunoprecipitation followed by sequencing (ChIP-seq) analyses revealed that the BAH domain of BAHCC1 specifically engage H3K27me3 through a hydrophobic trimethyl-lysine-binding cage and multiple intermolecular interactions to its flanking residues, mediating co-localization of BAHCC1 with H3K27me3-marked genomic regions in cells. Additionally, we find that BAHCC1 is overexpressed in several human leukemia subtypes including T-cell acute lymphoblastic leukemia (T-ALL), and interacts with transcriptional repressors SAP30-binding protein (SAP30BP) and histone deacetylase 1 (HDAC1). BAHCC1 loss, or disrupting the BAH-mediated interaction of BAHCC1 with H3K27me3 via structure-based mutagenesis, causes chromatin remodeling at the H3K27me3-targeted loci and reactivates polycomb-related gene-silencing programs intimately associated with tumor suppression and cell differentiation, which leads to significantly suppressed T-ALL tumor growth in vitro and in vivo.

2020-09-28 | GSE151576 | GEO

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

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

| PRJNA702926 | ENA

BAHCC1 couples H3K27me3 to gene silencing and tumorigenesis via a conserved BAH module [GW760_K27me3_ChIPseq]

Project description:Tri-methylation of histone H3 lysine 27 (H3K27me3) regulates transcriptional repression, cell-fate determination and differentiation. We report that a conserved Bromo-Adjacent Homology (BAH) module harbored within BAHCC1, a previously uncharacterized chromatin regulator, ‘recognizes’ H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and ChIP-seq-based analyses demonstrate that direct ‘readout’ of H3K27me3 by BAHCC1 is achieved through a hydrophobic trimethyl-lysine-binding ‘cage’ formed by the BAH domain, mediating co-localization of BAHCC1 and H3K27me3-marked genes. BAHCC1 is significantly overexpressed in human acute leukemia and biochemically, BAHCC1 interacts with repressors SAP30BP and HDAC. In acute leukemia, depletion of BAHCC1, or disruption of the BAHCC1 BAH-mediated ‘readout’ of H3K27me3, causes de-repression of H3K27me3-targeted genes that are involved in tumor suppression and cell differentiation, leading to the suppressed tumor growth. In mice, introduction of a germ-line mutation at Bahcc1 to disrupt its H3K27me3 engagement causes postnatal lethality, supporting a role of this pathway in development. Collectively, this study unveils a novel H3K27me3-directed transduction pathway in mammal cells that relies on a conserved BAH ‘reader’, deregulation of which contributes to oncogenesis.

2020-09-28 | GSE151575 | GEO

BAHCC1 couples H3K27me3 to gene silencing and tumorigenesis via a conserved BAH module [BAHCC1_KD_k27me3_293_ChIPseq]

2020-09-28 | GSE151574 | GEO

BAHCC1 couples H3K27me3 to gene silencing and tumorigenesis via a conserved BAH module [Gw760_E2aPbx1_mouse_Rnaseq]

2020-09-28 | GSE151577 | GEO

BAHCC1 couples H3K27me3 to gene silencing and tumorigenesis via a conserved BAH module [Jurkat BAHCC1_H3Ac_ChIPseq]

2020-09-28 | GSE151573 | GEO

FBXO11-Mediated Proteolysis of BAHD1 Relieves PRC2-dependent Transcriptional Repression in Erythropoiesis

Project description:The histone mark H3K27me3 and its reader/writer Polycomb repressive complex 2 (PRC2) mediate widespread transcriptional repression in stem and progenitor cells. Mechanisms that regulate this activity are critical for tissue development but poorly understood. Here we show that the E3 ubiquitin ligase FBXO11 relieves PRC2-mediated repression during erythroid maturation by targeting its newly identified substrate BAHD1, an H3K27me3 reader that recruits transcriptional co-repressors. Erythroblasts lacking FBXO11 are developmentally delayed, with reduced expression of maturation-associated genes, most of which harbor bivalent histone marks (activating H3K4me3 and repressive H3K27me3), bind BAHD1, and fail to recruit the erythroid transcription factor GATA1. The BAHD1 complex interacts physically with PRC2 and depletion of either component restores FBXO11-deficient erythroid gene expression. Previous studies showed that FBXO11 promotes B-cell development and inhibits lymphomagenesis by degrading the transcriptional repressor BCL6. We show that in aggressive B-cell lymphoma lines, depletion of FBXO11 causes the accumulation of both BCL6 and BAHD1, and that suppression of BAHD1 slows cell expansion. Our studies identify BAHD1 as a novel effector of PRC2-mediated repression and reveal how a single E3 ubiquitin ligase eliminates PRC2 repression at developmentally poised bivalent genes during erythropoiesis. The FBXO11-BAHD1 regulatory axis may function in other developmental pathways, including B-lymphopoiesis and lymphomagenesis.

2020-12-31 | GSE115357 | GEO

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