Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome

Andrea J. Cohen, Alina Saiakhova, Olivia Corradin, Jennifer M. Luppino, Katreya Lovrenert, Cynthia F. Bartels, James J. Morrow, Stephen C. Mack, Gursimran Dhillon, Lydia Beard, Lois Myeroff, Matthew F. Kalady, Joseph Willis, James E. Bradner, Ruth A. Keri, Nathan A. Berger, Shondra M. Pruett-Miller, Sanford D. Markowitz and Peter C. Scacheri ()
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Andrea J. Cohen: Case Western Reserve University School of Medicine
Alina Saiakhova: Case Western Reserve University School of Medicine
Olivia Corradin: Case Western Reserve University School of Medicine
Jennifer M. Luppino: Case Western Reserve University School of Medicine
Katreya Lovrenert: Case Western Reserve University School of Medicine
Cynthia F. Bartels: Case Western Reserve University School of Medicine
James J. Morrow: Case Western Reserve University School of Medicine
Stephen C. Mack: Lerner Research Institute, Cleveland Clinic
Gursimran Dhillon: Case Western Reserve University School of Medicine
Lydia Beard: Case Comprehensive Cancer Center, Case Western Reserve University
Lois Myeroff: Case Comprehensive Cancer Center, Case Western Reserve University
Matthew F. Kalady: Lerner Research Institute, Cleveland Clinic
Joseph Willis: Case Western Reserve University School of Medicine
James E. Bradner: Dana-Farber Cancer Institute
Ruth A. Keri: Case Western Reserve University School of Medicine
Nathan A. Berger: Case Western Reserve University School of Medicine
Shondra M. Pruett-Miller: Genome Engineering and iPSC Center, Washington University
Sanford D. Markowitz: Case Western Reserve University School of Medicine
Peter C. Scacheri: Case Western Reserve University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract In addition to mutations in genes, aberrant enhancer element activity at non-coding regions of the genome is a key driver of tumorigenesis. Here, we perform epigenomic enhancer profiling of a cohort of more than forty genetically diverse human colorectal cancer (CRC) specimens. Using normal colonic crypt epithelium as a comparator, we identify enhancers with recurrently gained or lost activity across CRC specimens. Of the enhancers highly recurrently activated in CRC, most are constituents of super enhancers, are occupied by AP-1 and cohesin complex members, and originate from primed chromatin. Many activate known oncogenes, and CRC growth can be mitigated through pharmacologic inhibition or genome editing of these loci. Nearly half of all GWAS CRC risk loci co-localize to recurrently activated enhancers. These findings indicate that the CRC epigenome is defined by highly recurrent epigenetic alterations at enhancers which activate a common, aberrant transcriptional programme critical for CRC growth and survival.

Date: 2017
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DOI: 10.1038/ncomms14400

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