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

被引：235

作者：

Brocks, David ^{[1
]}

Schmidt, Christopher R. ^{[1
]}

Daskalakis, Michael ^{[1
,2
]}

Jang, Hyo Sik ^{[3
]}

Shah, Nakul M. ^{[3
]}

Li, Daofeng ^{[3
]}

Li, Jing ^{[3
]}

Zhang, Bo ^{[3
]}

Hou, Yiran ^{[3
]}

Laudato, Sara ^{[1
]}

Lipka, Daniel B. ^{[1
]}

Schott, Johanna ^{[4
,5
]}

Bierhoff, Holger ^{[6
,16
,17
]}

Assenov, Yassen ^{[1
]}

Helf, Monika ^{[1
]}

Ressnerova, Alzbeta ^{[1
]}

Islam, Md Saiful ^{[1
]}

Lindroth, Anders M. ^{[1
,18
]}

Haas, Simon ^{[7
,8
]}

Essers, Marieke ^{[7
,8
]}

Imbusch, Charles D. ^{[9
]}

Brors, Benedikt ^{[2
,9
]}

Oehme, Ina ^{[10
,11
]}

Witt, Olaf ^{[2
,10
,11
]}

Luebbert, Michael ^{[2
,12
]}

Mallm, Jan-Philipp ^{[13
,14
]}

Rippe, Karsten ^{[13
,14
]}

Will, Rainer ^{[15
]}

Weichenhan, Dieter ^{[1
]}

Stoecklin, Georg ^{[3
]}

Gerhaeuser, Clarissa ^{[1
]}

Oakes, Christopher C. ^{[1
,19
]}

Wang, Ting ^{[3
]}

Plass, Christoph ^{[1
,2
,15
]}

机构：

[1] DKFZ, Div Epigen & Canc Risk Factors, Heidelberg, Germany

[2] German Canc Res Consortium DKTK, Heidelberg, Germany

[3] Washington Univ, Sch Med, Dept Genet, Edison Family Ctr Genome Sci & Syst Biol, St Louis, MO 63110 USA

[4] Heidelberg Univ, Div Biochem 1, Ctr Biomed & Med Technol Mannheim CBTM, Med Fac Mannheim, Mannheim, Germany

[5] Heidelberg Univ ZMBH, Ctr Mol Biol, DKFZ ZMBH Alliance, Mannheim, Germany

[6] DKFZ ZMBH Alliance, Div Mol Biol Cell 2, DKFZ, Heidelberg, Germany

[7] Heidelberg Inst Stem Cell Technol & Expt Med HI S, Heidelberg, Germany

[8] DKFZ, Div Stem Cells & Canc, Jr Res Grp Stress Induced Activat Hematopoiet Ste, Heidelberg, Germany

[9] DKFZ, Div Appl Bioinformat, Heidelberg, Germany

[10] Univ Hosp, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany

[11] DKFZ, Clin Cooperat Unit Pediat Oncol, Heidelberg, Germany

[12] Univ Freiburg, Div Hematol Oncol & Stem Cell Transplantat, Fac Med, Dept Med,Med Ctr, Freiburg, Germany

[13] DKFZ, Res Grp Genome Org & Funct, Heidelberg, Germany

[14] BioQuant Heidelberg, Heidelberg, Germany

[15] DKFZ, Genom & Prote Core Facil, Heidelberg, Germany

[16] Friedrich Schiller Univ, Dept Biochem, Inst Biochem & Biophys, CMB, Jena, Germany

[17] Fritz Lipmann Inst, Leibniz Inst Aging, Jena, Germany

[18] Natl Canc Ctr, Grad Sch Canc Sci & Policy, Goyang Si, South Korea

[19] Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA

来源：

NATURE GENETICS | 2017年 / 49卷 / 07期

关键词：

DIFFERENTIAL EXPRESSION ANALYSIS; ENDOGENOUS RETROVIRUS; DEMETHYLATING AGENTS; REGULATORY ELEMENTS; NONCODING RNAS; CANCER; IDENTIFICATION; GENES; CELLS; AML;

D O I：

10.1038/ng.3889

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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.

引用

页码：1052 / +

页数：12

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