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

Author

Listed:
  • Mizuo Ando

    (University of California San Diego
    University of Tokyo)

  • Yuki Saito

    (University of California San Diego
    University of Tokyo)

  • Guorong Xu

    (University of California San Diego)

  • Nam Q. Bui

    (University of California San Diego
    Stanford University School of Medicine)

  • 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
    Russian Academy of Sciences)

  • 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
    University of California San Diego)

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.

Suggested Citation

  • 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 & , 2019. "Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09937-w
    DOI: 10.1038/s41467-019-09937-w
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    Cited by:

    1. Morten Tulstrup & Mette Soerensen & Jakob Werner Hansen & Linn Gillberg & Maria Needhamsen & Katja Kaastrup & Kristian Helin & Kaare Christensen & Joachim Weischenfeldt & Kirsten Grønbæk, 2021. "TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis," Nature Communications, Nature, vol. 12(1), pages 1-10, December.

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