Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells.

Published online

Journal Article

The intestinal epithelium serves critical physiologic functions that are shared among all vertebrates. However, it is unknown how the transcriptional regulatory mechanisms underlying these functions have changed over the course of vertebrate evolution. We generated genome-wide mRNA and accessible chromatin data from adult intestinal epithelial cells (IECs) in zebrafish, stickleback, mouse, and human species to determine if conserved IEC functions are achieved through common transcriptional regulation. We found evidence for substantial common regulation and conservation of gene expression regionally along the length of the intestine from fish to mammals and identified a core set of genes comprising a vertebrate IEC signature. We also identified transcriptional start sites and other putative regulatory regions that are differentially accessible in IECs in all 4 species. Although these sites rarely showed sequence conservation from fish to mammals, surprisingly, they drove highly conserved IEC expression in a zebrafish reporter assay. Common putative transcription factor binding sites (TFBS) found at these sites in multiple species indicate that sequence conservation alone is insufficient to identify much of the functionally conserved IEC regulatory information. Among the rare, highly sequence-conserved, IEC-specific regulatory regions, we discovered an ancient enhancer upstream from her6/HES1 that is active in a distinct population of Notch-positive cells in the intestinal epithelium. Together, these results show how combining accessible chromatin and mRNA datasets with TFBS prediction and in vivo reporter assays can reveal tissue-specific regulatory information conserved across 420 million years of vertebrate evolution. We define an IEC transcriptional regulatory network that is shared between fish and mammals and establish an experimental platform for studying how evolutionarily distilled regulatory information commonly controls IEC development and physiology.

Full Text

Duke Authors

Cited Authors

  • Lickwar, CR; Camp, JG; Weiser, M; Cocchiaro, JL; Kingsley, DM; Furey, TS; Sheikh, SZ; Rawls, JF

Published Date

  • August 2017

Published In

Volume / Issue

  • 15 / 8

Start / End Page

  • e2002054 -

PubMed ID

  • 28850571

Pubmed Central ID

  • 28850571

Electronic International Standard Serial Number (EISSN)

  • 1545-7885

Digital Object Identifier (DOI)

  • 10.1371/journal.pbio.2002054

Language

  • eng

Conference Location

  • United States