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

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Item Type:	Article
Title:	DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats
Creators Name:	Brocks, D., Schmidt, C.R., Daskalakis, M., Jang, H.S., Shah, N.M., Li, D., Li, J., Zhang, B., Hou, Y., Laudato, S., Lipka, D.B., Schott, J., Bierhoff, H., Assenov, Y., Helf, M., Ressnerova, A., Islam, M.S., Lindroth, A.M., Haas, S., Essers, M., Imbusch, C.D., Brors, B., Oehme, I., Witt, O., Lübbert, M., Mallm, J.P., Rippe, K., Will, R., Weichenhan, D., Stoecklin, G., Gerhäuser, C., Oakes, C.C., Wang, T. and Plass, C.
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-annotated 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.
Keywords:	Alternative Splicing, Benzimidazoles, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Death-Associated Protein Kinases, Epigenetic Repression, Exons, Gene Expression Profiling, Gene Silencing, Histone Code, Histone Deacetylase Inhibitors, Hydroxamic Acids, Introns, Nude Mice, Recombinant Fusion Proteins, RNA Interference, Terminal Repeat Sequences, Transcription Initiation Site, Tumor Cell Line, Vorinostat, Animals, Mice
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	49
Number:	7
Page Range:	1052-1060
Date:	July 2017
Additional Information:	Erratum in: Nat Genet 49(11): 1661
Official Publication:	https://doi.org/10.1038/ng.3889
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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