A conserved BAH module within mammalian BAHD1 connects H3K27me3 to Polycomb gene silencing

Abstract

Trimethylation of histone H3 lysine 27 (H3K27me3) is important for gene silencing and imprinting, (epi)genome organization and organismal development. In a prevalent model, the functional readout of H3K27me3 in mammalian cells is achieved through the H3K27me3-recognizing chromodomain harbored within the chromobox (CBX) component of canonical Polycomb repressive complex 1 (cPRC1), which induces chromatin compaction and gene repression. Here, we report that binding of H3K27me3 by a Bromo Adjacent Homology (BAH) domain harbored within BAH domain-containing protein 1 (BAHD1) is required for overall BAHD1 targeting to chromatin and for optimal repression of the H3K27me3-demarcated genes in mammalian cells. Disruption of direct interaction between BAHD1BAH and H3K27me3 by point mutagenesis leads to chromatin remodeling, notably, increased histone acetylation, at its Polycomb gene targets. Mice carrying an H3K27me3-interaction-defective mutation of Bahd1BAH causes marked embryonic lethality, showing a requirement of this pathway for normal development. Altogether, this work demonstrates an H3K27me3-initiated signaling cascade that operates through a conserved BAH 'reader' module within BAHD1 in mammals.

An unexpected histone chaperone function for the MIER1 histone deacetylase complex

“…It has previously been shown that the BAH domain from BAHD1 recognises H3 histone tails bearing a K27me3 modification ( 10 ). We confirmed this interaction using a fluorescence anisotropy assay (Supplementary Fig.…”

“…Genome-targeted HDAC complexes typically contain domains or sequence motifs, or accessory proteins that mediate interaction with chromatin ( 31 ). The MIER complex has been reported to associate with the chromodomain protein CDYL and the BAH domain protein BAHD1 ( 10, 13, 32 ). When we co-expressed MIER1 with HDAC1 and the BAH domain from BAHD1 we found that the endogenous protein C1QBP co-purified with the complex in apparently stoichiometric amounts.…”

“…BAH domains have been shown to mediate interaction both with intact nucleosomes and with specific histone marks such as H4K20me2 and H3K27me3 (17)(18)(19)(20). Both BAHCC1 and BAHD1 recognise H3K27me3 suggesting that they are "reader" domains acting downstream of the PRC2 complex (10,21). It is unclear, however, whether these BAH domains simply recognise the H3K27me3 histone mark, or whether they can bind to intact nucleosomes in an analogous fashion to the BAHcontaining proteins ORC1 and SIR3 (17,20).…”

“…HDACs 1 and 2 are highly homologous enzymes that are assembled into six distinct multiprotein complexes: NuRD, CoREST, Sin3A, MiDAC, RERE and MIER ( 2-7 ). There appears to be little or no redundancy between these complexes since mice lacking unique components typically die during embryogenesis ( 5, 8-10 ). Apart from the HDAC enzyme, the complexes differ in subunit composition, but often contain chromatin and/or transcription factor interaction activities.…”

Hypoxic condition induced H3K27me3 modification of the LncRNA Tmem235 promoter thus supporting apoptosis of BMSCs

“…Histone methylation is an important epigenetic modification that can regulate gene expression and mainly occurs at the lysine residues of histones [15,16]. The trimethylation of histone H3 lysine 27 (H3K27me3) modification is mainly regulated dynamically by intracellular lysine methyltransferases and demethylases [17,18].…”