DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats

David Brocks, Christopher R. Schmidt, Michael Daskalakis, Hyo Sik Jang, Nakul M. Shah, Daofeng Li, Jing Li, Bo Zhang, Yiran Hou, Sara Laudato, Daniel B. Lipka, Johanna Schott, Holger Bierhoff, Yassen Assenov, Monika Helf, Alzbeta Ressnerova, Md Saiful Islam, Anders M. Lindroth, Simon Haas, Marieke EssersCharles D. Imbusch, Benedikt Brors, Ina Oehme, Olaf Witt, Michael Lübbert, Jan Philipp Mallm, Karsten Rippe, Rainer Will, Dieter Weichenhan, Georg Stoecklin, Clarissa Gerhäuser, Christopher C. Oakes, Ting Wang, Christoph Plass

Research output: Contribution to journalArticlepeer-review

165 Scopus citations

Abstract

Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non- A nnotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.

Original languageEnglish
Pages (from-to)1052-1060
Number of pages9
JournalNature Genetics
Volume49
Issue number7
DOIs
StatePublished - Jul 1 2017

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