The nuclear receptor HNF4 drives a brush border gene program conserved across murine intestine, kidney, and embryonic yolk sac

Abstract

The brush border is comprised of microvilli surface protrusions on the apical surface of epithelia. This specialized structure greatly increases absorptive surface area and plays crucial roles in human health. However, transcriptional regulatory networks controlling brush border genes are not fully understood. Here, we identify that hepatocyte nuclear factor 4 (HNF4) transcription factor is a conserved and important regulator of brush border gene program in multiple organs, such as intestine, kidney and yolk sac. Compromised brush border gene signatures and impaired transport were observed in these tissues upon HNF4 loss. By ChIP-seq, we find HNF4 binds and activates brush border genes in the intestine and kidney. H3K4me3 HiChIP-seq identifies that HNF4 loss results in impaired chromatin looping between enhancers and promoters at gene loci of brush border genes, and instead enhanced chromatin looping at gene loci of stress fiber genes in the intestine. This study provides comprehensive transcriptional regulatory mechanisms and a functional demonstration of a critical role for HNF4 in brush border gene regulation across multiple murine epithelial tissues.

A reference single-cell regulomic and transcriptomic map of cynomolgus monkeys

“…7d ). For example, the TF HNF4A is a crucial regulator for enterocyte cell identity 53 , 54 . Motif analysis revealed that different TF binding motifs showed different degree of enrichment among cell clusters, with the motif enrichment of HNF4A and HNF4G showing the largest variance (Supplementary Fig.…”

A potent HNF4α agonist reveals that HNF4α controls genes important in inflammatory bowel disease and Paneth cells

“…The finding here that Paneth cell gene expression is strongly enhanced by NCT demonstrates an important role for HNF4α in that cell type. While HNF4a had a strong effect on Paneth cells, that did not appear to be due to direct effects on Paneth cell genes, as a study of ChIP-seq in the intestine did not identify genes expressed in Paneth cells [ 11 ]. Rather, genes expressed in the brush border epithelium appeared to be directly downstream of HNF4a.…”

“…In the intestine, genetic deletion of HNF4α leads to loss of mucin-associated genes, increased intestinal permeability, loss of intestinal stem cell renewal (PMID: 31759926) and predisposes to inflammatory bowel disease [ 10 ] as well as loss of brush border genes [ 11 ]. In humans, HNF4α mRNA was decreased in intestinal biopsies from patients with inflammatory bowel disease (IBD) and HNF4α has been linked to IBD in multiple GWAS studies [ 12 – 14 ].…”

Regulatory domains controlling high intestinal vitamin D receptor gene expression are conserved in mouse and human

“…Small intestine crypt and villi were isolated from the proximal 10 cm of small intestine using methods we have previously reported ( 45 ). Colonic mucosal scrapings were collected from the entire colon.…”