Transcriptional and chromatin profiles of duodenum epithelium upon HNF4 loss in mice by RNA-seq and ChIP-seq

We find that HNF4G is an intestine-particular HNF4 paralog, and works redundantly with HNF4A for driving intestinal differentiation by controlling chromatin accessibility and regulating thousands of transcripts particular to differentiated cells. Without HNF4s, cells fail to achieve a differentiated state. A positive feedback loop between HNF4 transcriptional regulation and BMP/SMAD signaling stabilizes differentiation, and the two inputs cooperatively activate differentiation gene expression. Transcriptional profiling was employed to identify HNF4-dependent gene expression in the mouse duodenal epithelium. A series of ChIP-seq experiments (Hnf4alpha, Hnf4gamma and H3K27ac-MNase) identified the HNF4 binding regions in mouse duodenal epithelium and discovered and validated extensive co-binding with Smad4 in CaCO2 cells and mouse duodenal epithelium.