HDAC1 is a key regulator of gene expression in cancer. We identified a critical role for HDAC1 in establishing the transcriptional dependencies essential for survival in chronic lymphocytic leukemia (CLL) by profiling HDAC1 with BRD4, H3K27Ac superenhancers, H4K9Ac, chromatin accessibility signatures, Pol2 measurements and expression signatures to generate a regulatory chromatin landscape. Superenhancers marked by high levels of acetylation and BRD4 paradoxically also recruited the highest levels of HDAC1. HDAC inhibition poisoned transcription at these loci to selectively disrupt B-cell transcription factors and B-cell receptor signaling. HDAC1 was also recruited genome-wide at promoters without superenhancers to repress expression; HDAC inhibition reverses silencing at these loci, which include key microRNA networks that reciprocally downregulate CLL specific survival and driver genes. Our work provides a compelling rationale for profiling HDAC1 across cancers to characterize its role in driving transcriptional dysregulation that is a hallmark of most cancers and develop epigenetic therapeutic strategies.
Vascular smooth muscle cell (SMC) state/phenotype transitions underlie neointimal hyperplasia (IH) predisposing to cardiovascular diseases. Bromodomain protein BRD4 is a histone acetylation reader and enhancer mark that co-activates transcription elongation. CCAAT enhancer binding protein delta (CEBPD) is a transcription factor typically studied in adipogenesis and immune cell differentiation. Here we investigated the association between BRD4 and CEBPD in SMC state transition.Chromatin immunoprecipitation sequencing (ChIPseq) showed enrichment of BRD4 and histone acetylation (H3K27ac) at Cebpd and enhancer in rat carotid arteries undergoing IH. In vitro, BRD4 silencing with siRNA reduced SMC expression of CEBPD. Bromodomain-1 but not bromodoamin-2 accounted for this BRD4 function. Endogenous BRD4 co-IP'ed with CEBPD; Cebpd promoter and enhancer DNA fragments co-IP'ed with CEBPD or endogenous BRD4 (ChIP-qPCR). These co-IPs were abolished by the BRD4 bromodomain blocker JQ1. TNFa upregulated both BRD4 and CEBPD. Silencing CEBPD averted TNFa-induced inflammatory SMC state transition (heightened IL-1b, IL6, and MCP-1 mRNA levels), so did JQ1. CEBPD overexpression increased PDGFRa preferentially over PDGFRb; so did TNFa, and JQ1 abolished TNFa's effect.Our data reveal a BRD4/CEBPD partnership that promotes CEBPD's own transcription and inflammatory SMC state transition, thus shedding new light on epigenetic reader and transcription factor cooperative actions in SMC pathobiology.
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