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

Mizuo Ando, Yuki Saito, Guorong Xu, Nam Q. Bui, Kate Medetgul-Ernar, Minya Pu, Kathleen Fisch, Shuling Ren, Akihiro Sakai, Takahito Fukusumi, Chao Liu, Sunny Haft, John Pang, Adam Mark, Daria A. Gaykalova, Theresa Guo, Alexander V. Favorov, Srinivasan Yegnasubramanian, Elana J. Fertig, Patrick Ha, Pablo Tamayo, Tatsuya Yamasoba, Trey Ideker, Karen Messer and Joseph A. Califano ()
Additional contact information
Mizuo Ando: University of California San Diego
Yuki Saito: University of California San Diego
Guorong Xu: University of California San Diego
Nam Q. Bui: University of California San Diego
Kate Medetgul-Ernar: University of California San Diego
Minya Pu: University of California San Diego
Kathleen 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 School of Medicine
Theresa Guo: Johns Hopkins University School of Medicine
Alexander V. Favorov: Johns Hopkins University School of Medicine
Srinivasan Yegnasubramanian: Johns Hopkins University School of Medicine
Elana J. Fertig: Johns Hopkins University School of Medicine
Patrick Ha: University of California San Francisco, 2380 Sutter St
Pablo Tamayo: University of California San Diego
Tatsuya Yamasoba: University of Tokyo
Trey Ideker: University of California San Diego
Karen Messer: University of California San Diego
Joseph A. Califano: University of California San Diego

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09937-w

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