Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells

Abstract

Author summary The epithelium lining the intestine is an ancient animal tissue that serves as a primary site of nutrient absorption and interaction with microbiota. Its formation and function require complex patterns of gene transcription that vary along the intestine and in specialized intestinal epithelial cell (IEC) subtypes. However, it is unknown how the underlying transcriptional regulatory mechanisms have changed over the course of vertebrate evolution. Here, we used genome-wide profiling of mRNA levels and chromatin accessibility to identify conserved IEC genes and regulatory regions in 4 vertebrate species (zebrafish, stickleback, mouse, and human) separated from a common ancestor by 420 million years. We identified substantial similarities in genes expressed along the vertebrate intestine. These data disclosed putative conserved transcription factor binding sites (TFBS) enriched in accessible chromatin near IEC genes and in regulatory sites with accessibility restricted to IECs. Fluorescent reporter assays in transparent zebrafish showed that these regions, which frequently lacked sequence conservation, were still capable of driving conserved expression patterns. We also found a highly conserved region near mammalian and fish hes1 sufficient to drive expression in a specific population of IECs with active Notch signaling. These results establish a platform to define the conserved transcriptional networks underlying vertebrate IEC physiology.