HNF4 factors control chromatin accessibility and are redundantly required for maturation of the fetal intestine

Abstract

As embryos mature, cells undergo remarkable transitions that are accompanied by shifts in transcription factor regulatory networks. Mechanisms driving developmental transitions are incompletely understood. The embryonic intestine transitions from a rapidly proliferating tube with pseudostratified epithelium prior to murine embryonic day (E) 14.5 to an exquisitely folded columnar epithelium in fetal stages. We sought to identify factors driving mouse fetal intestinal maturation by mining chromatin accessibility data for transcription factor motifs. ATAC-seq accessible regions shift during tissue maturation, with CDX2 transcription factor motifs abundant at chromatin-accessible regions of the embryo. Hepatocyte nuclear factor 4 (HNF4) transcription factor motifs are the most abundant in the fetal stages (>E16.5). Genetic inactivation of Hnf4a and its paralog Hnf4g revealed that HNF4 factors are redundantly required for fetal maturation. CDX2 binds to and activates Hnf4 gene loci to elevate HNF4 expression at fetal stages. HNF4 and CDX2 transcription factors then occupy shared genomic regulatory sites to promote chromatin accessibility and gene expression in the maturing intestine. Thus, HNF4 paralogs are key components of an intestinal transcription factor network shift during the embryonic to fetal transition.

Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1

“…Ingenuity pathway analysis (IPA) of the RNA-seq data from colitis-induced polyps suggested a transcription factor, hepatocyte nuclear factor 4-alpha (HNF4A) as an upstream regulator that is activated in the absence of DKK2 ( Figure S5 A). HNF4A is a nuclear receptor protein which is crucial for development of the gut ( Chen et al., 2019 ). Villin CreERT2- Hnf4a fl/fl conditional knockout mice showed destabilization of intestinal epithelium following increased expression of LGR5 upon tamoxifen administration ( Cattin et al., 2009 ).…”

Identification of Transcription Factors Regulating SARS-CoV-2 Entry Genes in the Intestine

“…CDX2 is required for specification of the intestine during embryonic development, 5 and in adult life is required for intestinal maturation and proper enterocyte function. 6 HNF4 factors are required for maturation of the embryonic intestine, 7 and work in conjunction with SMAD4 to promote expression of adult enterocyte genes. 8 GATA family transcription factors are important for intestinal regionalization.…”

Three-dimensional interactions between enhancers and promoters during intestinal differentiation depend upon HNF4

“…We found 25% of the genes significantly altered at the transcript level by 2-fold or more between Hnf4αγ DKO versus wild type (WT) (FPKM > 1, log 2 fold change [FC] > 1 or < −1) are also changed at the level of chromatin looping. We have reported previously that HNF4 factors are redundantly required to maintain accessible, active enhancer chromatin ( Chen et al, 2019a , 2019b ). Consistent with these previous findings, chromatin loops affected by HNF4 loss exhibited a corresponding change in enhancer chromatin properties ( Figure 3E ).…”