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

Mizuo Ando(University of California San Diego), Yuki Saito(University of California San Diego), Guorong Xu(University of California San Diego), Nam Q. Bui(Palo Alto University), Kate Medetgul-Ernar(University of California San Diego), Minya Pu(University of California San Diego), Kathleen M. Fisch(University of California San Diego), Shuling Ren(University of California San Diego), Akihiro Sakai(University of California San Diego), Takahito Fukusumi(University of California San Diego), Chao Liu(University of California San Diego), Sunny Haft(University of California San Diego), John Pang(University of California San Diego), Adam Mark(University of California San Diego), Daria A. Gaykalova(Johns Hopkins University), Theresa Guo(Johns Hopkins University), Alexander V. Favorov(Johns Hopkins University), Srinivasan Yegnasubramanian(Johns Hopkins University), Elana J. Fertig(Johns Hopkins University), Patrick K. Ha(University of California, San Francisco), Pablo Tamayo(University of California San Diego), Tatsuya Yamasoba(The University of Tokyo), Trey Ideker(University of California San Diego), Karen Messer(University of California San Diego), Joseph A. Califano(UC San Diego Health System)
Nature Communications
May 16, 2019
10.1038/s41467-019-09937-w
Cited by 109Open Access
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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.

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