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Nat Commun. 2019 May 16;10(1):2188. doi: 10.1038/s41467-019-09937-w.

Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers.

Author information

1
Moores Cancer Center, University of California San Diego, 3855 Health Sciences Dr, La Jolla, CA, 92093, USA.
2
Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
3
Department of Medicine, Center for Computational Biology and Bioinformatics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
4
Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
5
Department of Medicine (Oncology), Stanford University School of Medicine, 875 Blake Wilbur Dr, Palo Alto, CA, 94304, USA.
6
Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, 601 N Caroline St, Baltimore, MD, 21287, USA.
7
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 401 N Broadway, Baltimore, MD, 21231, USA.
8
Laboratory of Systems Biology and Computational Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkina str. 3, Moscow, 119333, Russia.
9
Department of Otolaryngology - Head and Neck Surgery, University of California San Francisco, 2380 Sutter St, San Francisco, CA, 94115, USA.
10
Moores Cancer Center, University of California San Diego, 3855 Health Sciences Dr, La Jolla, CA, 92093, USA. jcalifano@ucsd.edu.
11
Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, University of California San Diego, 9300 Campus Point Drive, La Jolla, CA, 92037, USA. jcalifano@ucsd.edu.

Abstract

Although promoter-associated CpG islands have been established as targets of DNA methylation changes in cancer, previous studies suggest that epigenetic dysregulation outside the promoter region may be more closely associated with transcriptional changes. Here we examine DNA methylation, chromatin marks, and transcriptional alterations to define the relationship between transcriptional modulation and spatial changes in chromatin structure. Using human papillomavirus-related oropharyngeal carcinoma as a model, we show aberrant enrichment of repressive H3K9me3 at the transcriptional start site (TSS) with methylation-associated, tumor-specific gene silencing. Further analysis identifies a hypermethylated subtype which shows a functional convergence on MYC targets and association with CREBBP/EP300 mutation. The tumor-specific shift to transcriptional repression associated with DNA methylation at TSSs was confirmed in multiple tumor types. Our data may show a common underlying epigenetic dysregulation in cancer associated with broad enrichment of repressive chromatin marks and aberrant DNA hypermethylation at TSSs in combination with MYC network activation.

PMID:
31097695
PMCID:
PMC6522544
DOI:
10.1038/s41467-019-09937-w
[Indexed for MEDLINE]
Free PMC Article

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