Three-dimensional analysis reveals altered chromatin interaction by enhancer inhibitors harbors TCF7L2-regulated cancer gene signature. J Cell Biochem 2019 Mar;120(3):3056-3070
Date
12/15/2018Pubmed ID
30548288Pubmed Central ID
PMC6476548DOI
10.1002/jcb.27449Scopus ID
2-s2.0-85058244236 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
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.
Author List
Gerrard DL, Wang Y, Gaddis M, Zhou Y, Wang J, Witt H, Lin S, Farnham PJ, Jin VX, Frietze SEAuthor
Victor X. Jin PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
BenzoatesBridged Bicyclo Compounds, Heterocyclic
Cell Line, Tumor
Chromatin
Chromatin Assembly and Disassembly
Chromosome Mapping
Epigenesis, Genetic
Epigenomics
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
Nitrobenzenes
Pancreatic Neoplasms
Pyrazoles
Pyrazolones
Pyrimidinones
Transcription Factor 7-Like 2 Protein
