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

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. Examination of the genome-wide distribution of H3K27me3, H3K9ac, H3K27ac and H3K9me3 in HEK293 cells with stable expression of an exogenous BAHD1, either wildtype (WT) or BAH-mutated (i.e., W667G), followed by knockdown (KD) of endogenous BAHD1.