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

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: Examination of genome-wide binding for wild-type (WT) BAHCC1 in Jurkat T-ALL cells with knockin (KI) of a 3xFlag tag into C-terminus of endogenous BAHCC1 gene locus; parental Jurkat cells without KI of tag were used as negative control for Flag-BAHCC1 ChIP-seq. The same 3xFlag tag KI strategy was used for examining genome-wide binding of a BAH-mutated (Y2533A) form of BAHCC1 in Jurkat cells. We also examined genome-wide H3 acetylation (H3Ac) levels in the Jurkat cells with either WT BAHCC1 or the homozygous mutations of the BAHCC1 BAH domain (i.e., W2554G). We also sequenced the input chromatin sample of parental Jurkat cells (kindly provided by Drs. D Schuermann and P Schär) that matches the GSM2279072 H3K27me3 dataset used in the study.