BAHCC1 couples H3K27me3 to gene silencing and tumorigenesis via a conserved BAH module [Gw760_E2aPbx1_mouse_Rnaseq]
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. Overall design: Transcriptome profilings of the E2a-Pbx1-transformed murine acute leukemia lines, which were established by using primary hematopoietic stem/progenitor cells (HSPCs) derived from bone marrow of either WT mice or those carrying the engineered homozygous mutations of the Bahcc1 BAH domain (i.e., Y2537A).