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 HaPablo Tamayo, Tatsuya Yamasoba, Trey Ideker, Karen Messer, Joseph A. Califano

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number2188
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Ando, M., Saito, Y., Xu, G., Bui, N. Q., Medetgul-Ernar, K., Pu, M., Fisch, K., Ren, S., Sakai, A., Fukusumi, T., Liu, C., Haft, S., Pang, J., Mark, A., Gaykalova, D. A., Guo, T., Favorov, A. V., Yegnasubramanian, S., Fertig, E. J., ... Califano, J. A. (2019). Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers. Nature communications, 10(1), [2188]. https://doi.org/10.1038/s41467-019-09937-w