Hepatocyte nuclear factor-1β recruits the nucleosome remodeling and deacetylase complex to activate gene transcription

Abstract

Mutations affecting the transcription factor hepatocyte nuclear factor-1{beta} (HNF-1{beta}) are the most common monogenic cause of congenital anomalies of the kidney and urinary tract. The mechanism whereby HNF-1{beta} regulates gene transcription remains unclear. Here, we performed an unbiased proteomic screen and found that endogenous HNF-1{beta} interacts with core subunits of the nucleosome remodeling and deacetylase complex (NuRD) in renal epithelial cells. Genome-wide ChIP-seq studies demonstrated colocalization of endogenous HNF-1{beta} and the core NuRD subunits GATAD2A, CHD4, and MBD3 at 2,776 primarily intergenic and intronic sites in native chromatin from wild-type renal epithelial cells. NuRD co-occupancy at 628 of the sites (22.6%) was reduced in the absence of HNF-1{beta}. Of the 628 HNF-1{beta}-dependent NuRD-occupied sites, 113 sites (18.2%) showed higher ATAC-seq peaks, indicative of open chromatin, and enrichment of histone H3 lysine-27 (H3K27) acetylation, indicative of active enhancers, in wild-type cells compared to HNF-1{beta}-deficient cells. Correlation with transcriptomic profiles in wild-type and HNF-1{beta}-deficient cells revealed that most of the sites were located near genes that are activated by HNF-1{beta}. Knockdown of CHD4 with shRNA resulted in decreased expression of 67 HNF-1{beta}-regulated genes that contained nearby NuRD and HNF-1{beta} co-occupied sites. Collectively, these results demonstrate that HNF-1{beta} recruits the NuRD complex resulting in H3K27 acetylation and chromatin opening and leading to gene activation. Our findings reveal a new mechanism of HNF-1{beta}-dependent gene expression and expand the role of the NuRD complex in gene activation at distal enhancers.