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

As embryos mature, cells undergo remarkable transitions, 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 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, and hepatocyte nuclear factor 4 (HNF4) transcription factor motifs the most abundant in the fetal stages (> E 16.5). Genetic inactivation of Hnf4α and its paralog, Hnf4γ, 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.