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Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells.

Publication ,  Journal Article
Lickwar, CR; Camp, JG; Weiser, M; Cocchiaro, JL; Kingsley, DM; Furey, TS; Sheikh, SZ; Rawls, JF
Published in: PLoS Biol
August 2017

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.

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Published In

PLoS Biol

DOI

EISSN

1545-7885

Publication Date

August 2017

Volume

15

Issue

8

Start / End Page

e2002054

Location

United States

Related Subject Headings

  • Zebrafish
  • Species Specificity
  • Smegmamorpha
  • Rivers
  • RNA, Messenger
  • Organ Specificity
  • Mice
  • Male
  • Larva
  • Jejunum
 

Citation

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Lickwar, C. R., Camp, J. G., Weiser, M., Cocchiaro, J. L., Kingsley, D. M., Furey, T. S., … Rawls, J. F. (2017). Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells. PLoS Biol, 15(8), e2002054. https://doi.org/10.1371/journal.pbio.2002054
Lickwar, Colin R., J Gray Camp, Matthew Weiser, Jordan L. Cocchiaro, David M. Kingsley, Terrence S. Furey, Shehzad Z. Sheikh, and John F. Rawls. “Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells.PLoS Biol 15, no. 8 (August 2017): e2002054. https://doi.org/10.1371/journal.pbio.2002054.
Lickwar CR, Camp JG, Weiser M, Cocchiaro JL, Kingsley DM, Furey TS, et al. Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells. PLoS Biol. 2017 Aug;15(8):e2002054.
Lickwar, Colin R., et al. “Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells.PLoS Biol, vol. 15, no. 8, Aug. 2017, p. e2002054. Pubmed, doi:10.1371/journal.pbio.2002054.
Lickwar CR, Camp JG, Weiser M, Cocchiaro JL, Kingsley DM, Furey TS, Sheikh SZ, Rawls JF. Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells. PLoS Biol. 2017 Aug;15(8):e2002054.
Journal cover image

Published In

PLoS Biol

DOI

EISSN

1545-7885

Publication Date

August 2017

Volume

15

Issue

8

Start / End Page

e2002054

Location

United States

Related Subject Headings

  • Zebrafish
  • Species Specificity
  • Smegmamorpha
  • Rivers
  • RNA, Messenger
  • Organ Specificity
  • Mice
  • Male
  • Larva
  • Jejunum