TY - JOUR
T1 - Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers
AU - Ando, Mizuo
AU - Saito, Yuki
AU - Xu, Guorong
AU - Bui, Nam Q.
AU - Medetgul-Ernar, Kate
AU - Pu, Minya
AU - Fisch, Kathleen
AU - Ren, Shuling
AU - Sakai, Akihiro
AU - Fukusumi, Takahito
AU - Liu, Chao
AU - Haft, Sunny
AU - Pang, John
AU - Mark, Adam
AU - Gaykalova, Daria A.
AU - Guo, Theresa
AU - Favorov, Alexander V.
AU - Yegnasubramanian, Srinivasan
AU - Fertig, Elana J.
AU - Ha, Patrick
AU - Tamayo, Pablo
AU - Yamasoba, Tatsuya
AU - Ideker, Trey
AU - Messer, Karen
AU - Califano, Joseph A.
N1 - Funding Information:
We thank Bing Ren, and Naoki Nariai for insightful comments and discussions. Without their encouragement, this paper would not have materialized. The authors also thank Sayed Sadat for technical assistance. This work was supported by JSPS KAKENHI 15KK0334 (M. Ando), NIH UL1TR001442 of CTSA (K. Fisch), NIH R01DE023347 (J. Califano), and NIH P50DE019032 (J. Califano).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-019-09937-w
DO - 10.1038/s41467-019-09937-w
M3 - Article
C2 - 31097695
AN - SCOPUS:85065779800
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2188
ER -
