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

Cells in renewing tissues exhibit dramatic transcriptional changes as they differentiate. The contribution of chromatin looping to tissue renewal is incompletely understood. Enhancer-promoter interactions could be relatively stable as cells transition from progenitor to differentiated states; alternatively, chromatin looping could be as dynamic as the gene expression from their loci. The intestinal epithelium is the most rapidly renewing mammalian tissue. Proliferative cells in crypts of Lieberkuhn sustain a stream of differentiated cells that are continually shed into the lumen. We apply chromosome conformation capture combined with chromatin immunoprecipitation (HiChIP) and sequencing to measure enhancer-promoter interactions in progenitor and differentiated cells of the intestinal epithelium. Despite dynamic gene regulation across the differentiation axis, we find that enhancer-promoter interactions are relatively stable. Functionally, we find HNF4 transcription factors are required for chromatin looping at target genes. Depletion of HNF4 disrupts local chromatin looping, histone modifications, and target gene expression. This study provides insights into transcriptional regulatory mechanisms governing homeostasis in renewing tissues.

Automated summary

In renewing tissues like the intestinal epithelium, enhancer-promoter interactions remain relatively stable despite dynamic gene regulation across the differentiation axis. HNF4 transcription factors are found to be essential for chromatin looping at target genes, with depletion of HNF4 disrupting local chromatin looping, histone modifications, and target gene expression. This study offers insights into the transcriptional regulatory mechanisms governing homeostasis in renewing tissues.