@article{2f5f07c787d24269817afbecbf4ef6be,
title = "DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats",
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.",
author = "David Brocks and Schmidt, {Christopher R.} and Michael Daskalakis and Jang, {Hyo Sik} and Shah, {Nakul M.} and Daofeng Li and Jing Li and Bo Zhang and Yiran Hou and Sara Laudato and Lipka, {Daniel B.} and Johanna Schott and Holger Bierhoff and Yassen Assenov and Monika Helf and Alzbeta Ressnerova and Islam, {Md Saiful} and Lindroth, {Anders M.} and Simon Haas and Marieke Essers and Imbusch, {Charles D.} and Benedikt Brors and Ina Oehme and Olaf Witt and Michael L{\"u}bbert and Mallm, {Jan Philipp} and Karsten Rippe and Rainer Will and Dieter Weichenhan and Georg Stoecklin and Clarissa Gerh{\"a}user and Oakes, {Christopher C.} and Ting Wang and Christoph Plass",
note = "Funding Information: We thank C. Weigel, R. Toth, and K. Chiappinelli for helpful feedback and discussions and A. Tanay for critical proofreading of the manuscript. We also thank K. Bauer, K. Klimo, M. B{\"a}hr and the Genomics and Proteomics Core Facility at the German Cancer Research Center for their excellent technical support and expertise. D.B. is supported by the German-Israeli Helmholtz Research School in Cancer Biology. D.L., J.L., H.S.J., B.Z., and T.W. are supported by the American Cancer Society grant RSG-14-049-01-DMC and NIH grants R01HG007354, R01HG007175, R01ES024992, U01CA200060, U01HG009391, and U24ES 026699. This work was supported in part by the Helmholtz Association, the DFG funded Priority Program SPP1463, the German Center for Lung Research (DZL), and BMBF funded CancerEpiSys program and the ICGC Data-Mining project. Publisher Copyright: {\textcopyright} 2017 Nature America, Inc., part of Springer Nature. All rights reserved.",
year = "2017",
month = jul,
day = "1",
doi = "10.1038/ng.3889",
language = "English",
volume = "49",
pages = "1052--1060",
journal = "Nature Genetics",
issn = "1061-4036",
number = "7",
}