BioProject

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. More...

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. Overall design: Transcriptome profilings of the Jurkat T-cell acute lymphoblastic leukemia (T-ALL) cells with stable expression of a BAHCC1-targeting shRNA (either sh988 or sh993) versus empty vector (shEV), Jurkat cells post-treatment with UNC1999 (an EZH2/EZH1 small-molecule inhibitor) versus DMSO, as well as the Jurkat cells with either wildtype BAHCC1 allele (WT) or the homozygous mutations of the BAHCC1 BAH domain (W2554G introduced into a non-luciferase-labeled Jurkat line, or Y2533A introduced into a luciferase-GFP-labeled Jurkat line). Transcriptome profiling of the RS4;11 B-cell ALL cells with stable expression of the BAHCC1-targeting shRNA (sh988) versus shEV. Transcriptome profiling of the OCI-AML3 acute myeloid leukemia (AML) cells with stable expression of the BAHCC1-targeting shRNA (sh988) versus shEV.. Less...