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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151576 | GEO | 2020/09/28

REPOSITORIES: GEO