BAHD1 links H3K27me3 to gene silencing via a conserved BAH reader module and associated corepressor complex in mammalian cells (CUT&RUN)

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-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 that contains histone deacetylase 1/2 (HDAC1/2) and MIER1/2/3. Abolishing the BAHD1BAH:H3K27me3 interaction by point mutagenesis interferes with BAHD1 binding to chromatin, resulting in chromatin remodeling at target genes and derepression of Polycomb-related genes. Mice carrying an H3K27me3-association-defective mutation at 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.