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

• Published in: Journal of cellular biochemistry Vol. 120; no. 3; pp. 3056 - 3070
• Main Authors: Gerrard, Diana L., Wang, Yao, Gaddis, Malaina, Zhou, Yufan, Wang, Junbai, Witt, Heather, Lin, Shili, Farnham, Peggy J., Jin, Victor X., Frietze, Seth E.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2019
• Subjects: Acetylation; altered chromatin interaction; Architecture; Benzoates - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cancer; Cell Line, Tumor; Chromatin; Chromatin - chemistry; Chromatin - genetics; Chromatin - metabolism; Chromatin Assembly and Disassembly; Chromosome Mapping; Chromosomes; Conformation; Dimensional analysis; Domains; Epigenesis, Genetic - drug effects; Epigenetics; Epigenomics; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene regulation; Gene Regulatory Networks - drug effects; Genes; Genomes; Histone acetyltransferase; histone acetyltransferase (HAT); Humans; Identification methods; Inhibitors; Mathematical analysis; Pancreatic cancer; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pyrazoles - pharmacology; Pyrimidinones - pharmacology; Regulatory sequences; Ribonucleic acid; RNA; TCF7L2; tethered chromatin capture (TCC); Transcription Factor 7-Like 2 Protein - genetics; Transcription Factor 7-Like 2 Protein - metabolism; TCF7L2; histone acetyltransferase (HAT); chromatin; altered chromatin interaction; tethered chromatin capture (TCC); pancreatic ductal adenocarcinoma
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.27449

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. We applied a developed an integrative approach for analysis higher order chromatin data to identify domains can classify dynamic chromatin looping events. With the use of epigenetic inhibitors, our work also provides insights into the interdependence of 3D chromatin looping and transcriptional control.