Three-dimensional analysis reveals altered chromatin interaction by enhancer inhibitors harbors TCF7L2-regulated cancer gene signature

Diana L. Gerrard, Yao Wang, Malaina Gaddis, Yufan Zhou, Junbai Wang, Heather Witt, Shili Lin, Peggy J. Farnham, Victor X. Jin, Seth E. Frietze

Research output: Contribution to journalArticle

Abstract

Distal regulatory elements influence the activity of gene promoters through chromatin looping. Chromosome conformation capture (3C) methods permit identification of chromatin contacts across different regions of the genome. However, due to limitations in the resolution of these methods, the detection of functional chromatin interactions remains a challenge. In the current study, we employ an integrated approach to define and characterize the functional chromatin contacts of human pancreatic cancer cells. We applied tethered chromatin capture to define classes of chromatin domains on a genome-wide scale. We identified three types of structural domains (topologically associated, boundary, and gap) and investigated the functional relationships of these domains with respect to chromatin state and gene expression. We uncovered six distinct sub-domains associated with epigenetic states. Interestingly, specific epigenetically active domains are sensitive to treatment with histone acetyltransferase (HAT) inhibitors and decrease in H3K27 acetylation levels. To examine whether the subdomains that change upon drug treatment are functionally linked to transcription factor regulation, we compared TCF7L2 chromatin binding and gene regulation to HAT inhibition. We identified a subset of coding RNA genes that together can stratify pancreatic cancer patients into distinct survival groups. Overall, this study describes a process to evaluate the functional features of chromosome architecture and reveals the impact of epigenetic inhibitors on chromosome architecture and identifies genes that may provide insight into disease outcome.

Original languageEnglish (US)
Pages (from-to)3056-3070
Number of pages15
JournalJournal of Cellular Biochemistry
Volume120
Issue number3
DOIs
StatePublished - Mar 2019

Keywords

  • TCF7L2
  • altered chromatin interaction
  • chromatin
  • histone acetyltransferase (HAT)
  • pancreatic ductal adenocarcinoma
  • tethered chromatin capture (TCC)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Gerrard, D. L., Wang, Y., Gaddis, M., Zhou, Y., Wang, J., Witt, H., Lin, S., Farnham, P. J., Jin, V. X., & Frietze, S. E. (2019). Three-dimensional analysis reveals altered chromatin interaction by enhancer inhibitors harbors TCF7L2-regulated cancer gene signature. Journal of Cellular Biochemistry, 120(3), 3056-3070. https://doi.org/10.1002/jcb.27449