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J Cell Biochem. 2019 Mar;120(3):3056-3070. doi: 10.1002/jcb.27449. Epub 2018 Dec 11.

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

Author information

1
Biomedical Health Sciences Department, University of Vermont, Burlington, VT, USA.
2
Cellular, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington, VT, USA.
3
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
4
Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA.
5
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
6
Department of Pathology, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.
7
Statistics Department, The Ohio State University, Columbus, OH, USA.
8
The University of Vermont Cancer Center, Burlington, VT, USA.

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.

KEYWORDS:

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

PMID:
30548288
DOI:
10.1002/jcb.27449

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