CoChat
Sign Up
Cited by 339Epigenetics and DNA MethylationGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

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

Open access
Brocks, David, Schmidt, Christopher R, Daskalakis, Michael, Jang, Hyo Sik, Shah, Nakul M, Li, Daofeng, Li, Jing, Zhang, Bo +26 more·2017·Nature Genetics
DOI 10.1038/ng.3889PMC PMC6005702
Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/ng.3889

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 64

  1. [1]Navada SC Steinmann J Lubbert M Silverman LR Clinical development of demethylating agents in hematology The Journal of clinical investigation 124 40 46 10.1172/JCI69739 2014 24382388 PMC3871232 · DOI
  2. [2]West AC Johnstone RW New and emerging HDAC inhibitors for cancer treatment The Journal of clinical investigation 124 30 39 10.1172/JCI69738 2014 24382387 PMC3871231 · DOI · Paper page
  3. [3]Jones PA At the tipping point for epigenetic therapies in cancer The Journal of clinical investigation 124 14 16 10.1172/JCI74145 2014 24382384 PMC3871262 · DOI
  4. [5]Roulois D DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts Cell 162 961 973 10.1016/j.cell.2015.07.056 2015 26317465 PMC4843502 · DOI · Paper page
  5. [6]Li H Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers Oncotarget 5 587 598 10.18632/oncotarget.1782 2014 24583822 PMC3996658 · DOI
  6. [7]Cameron EE Bachman KE Myohanen S Herman JG Baylin SB Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer Nature genetics 21 103 107 10.1038/5047 1999 9916800 · DOI
  7. [9]Pertea M StringTie enables improved reconstruction of a transcriptome from RNA-seq reads Nature biotechnology 33 290 295 10.1038/nbt.3122 2015 PMC4643835 25690850 · DOI
  8. [10]Iyer MK The landscape of long noncoding RNAs in the human transcriptome Nature genetics 47 199 208 10.1038/ng.3192 2015 25599403 PMC4417758 · DOI · Paper page
  9. [11]Prensner JR The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex Nature genetics 45 1392 1398 10.1038/ng.2771 2013 24076601 PMC3812362 · DOI
  10. [12]Almeida LG CTdatabase: a knowledge-base of high-throughput and curated data on cancer-testis antigens Nucleic acids research 37 D816 819 10.1093/nar/gkn673 2009 18838390 PMC2686577 · DOI
  11. [14]van Heesch S Extensive localization of long noncoding RNAs to the cytosol and mono-and polyribosomal complexes Genome biology 15 R6 10.1186/gb-2014-15-1-r6 2014 24393600 PMC4053777 · DOI
  12. [15]Xie M DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape Nature genetics 45 836 841 10.1038/ng.2649 2013 23708189 PMC3695047 · DOI
  13. [16]Goke J Dynamic transcription of distinct classes of endogenous retroviral elements marks specific populations of early human embryonic cells Cell stem cell 16 135 141 10.1016/j.stem.2015.01.005 2015 25658370 · DOI
  14. [17]Rafehi H Vascular histone deacetylation by pharmacological HDAC inhibition Genome research 24 1271 1284 10.1101/gr.168781.113 2014 24732587 PMC4120081 · DOI
  15. [19]Sokol M Jessen KM Pedersen FS Human endogenous retroviruses sustain complex and cooperative regulation of gene-containing loci and unannotated megabase-sized regions Retrovirology 12 32 10.1186/s12977-015-0161-9 2015 25927889 PMC4422309 · DOI
  16. [20]Hashimoto K CAGE profiling of ncRNAs in hepatocellular carcinoma reveals widespread activation of retroviral LTR promoters in virus-induced tumors Genome research 10.1101/gr.191031.115 2015 PMC4665003 26510915 · DOI · Paper page
  17. [21]Yu XP The long terminal repeat (LTR) of ERV-9 human endogenous retrovirus binds to NF-Y in the assembly of an active LTR enhancer complex NF-Y/MZF1/GATA-2 J Biol Chem 280 35184 35194 10.1074/jbc.M508138200 2005 16105833 · DOI
  18. [22]New M Olzscha H La Thangue NB HDAC inhibitor-based therapies: can we interpret the code? Molecular oncology 6 637 656 10.1016/j.molonc.2012.09.003 2012 23141799 PMC5528347 · DOI
  19. [23]Klco JM Genomic impact of transient low-dose decitabine treatment on primary AML cells Blood 121 1633 1643 10.1182/blood-2012-09-459313 2013 23297133 PMC3587326 · DOI
  20. [24]de Parseval N Lazar V Casella JF Benit L Heidmann T Survey of human genes of retroviral origin: identification and transcriptome of the genes with coding capacity for complete envelope proteins Journal of virology 77 10414 10422 2003 12970426 PMC228468
  21. [25]Katoh I Kurata S Association of endogenous retroviruses and long terminal repeats with human disorders Frontiers in oncology 3 234 10.3389/fonc.2013.00234 2013 24062987 PMC3769647 · DOI
  22. [26]Lander ES Initial sequencing and analysis of the human genome Nature 409 860 921 10.1038/35057062 2001 11237011 · DOI · Paper page
  23. [27]La Mantia G Identification of regulatory elements within the minimal promoter region of the human endogenous ERV9 proviruses: accurate transcription initiation is controlled by an Inr-like element Nucleic acids research 20 4129 4136 1992 1508707 PMC334116
  24. [28]Lania L Structural and functional organization of the human endogenous retroviral ERV9 sequences Virology 191 464 468 1992 1413518
  25. [29]Ling J The solitary long terminal repeats of ERV-9 endogenous retrovirus are conserved during primate evolution and possess enhancer activities in embryonic and hematopoietic cells Journal of virology 76 2410 2423 2002 11836419 PMC153808
  26. [30]Pi W Long-range function of an intergenic retrotransposon Proceedings of the National Academy of Sciences of the United States of America 107 12992 12997 10.1073/pnas.1004139107 2010 20615953 PMC2919959 · DOI
  27. [31]Kronung SK LTR12 promoter activation in a broad range of human tumor cells by HDAC inhibition Oncotarget 7 33484 33497 10.18632/oncotarget.9255 2016 27172897 PMC5085097 · DOI
  28. [32]Beyer U Kronung SK Leha A Walter L Dobbelstein M Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death Cell death and differentiation 23 64 75 10.1038/cdd.2015.68 2016 26024393 PMC4815979 · DOI
  29. [33]Sherrill-Mix S Ocwieja KE Bushman FD Gene activity in primary T cells infected with HIV89.6: intron retention and induction of genomic repeats Retrovirology 12 79 10.1186/s12977-015-0205-1 2015 26377088 PMC4574318 · DOI
  30. [34]Lock FE Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma Proceedings of the National Academy of Sciences of the United States of America 111 E3534 3543 10.1073/pnas.1405507111 2014 25114248 PMC4151764 · DOI
  31. [35]Mak KS Repression of chimeric transcripts emanating from endogenous retrotransposons by a sequence-specific transcription factor Genome biology 15 R58 10.1186/gb-2014-15-4-r58 2014 24946810 PMC4056533 · DOI
  32. [36]Wiesner T Alternative transcription initiation leads to expression of a novel ALK isoform in cancer Nature 526 453 457 10.1038/nature15258 2015 26444240 PMC4807020 · DOI
  33. [37]Vizoso M Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR Nature medicine 21 741 750 10.1038/nm.3863 2015 PMC4968631 26030178 · DOI
  34. [38]Chiappinelli KB Zahnow CA Ahuja N Baylin SB Combining Epigenetic and Immunotherapy to Combat Cancer Cancer research 10.1158/0008-5472.CAN-15-2125 2016 PMC4873370 26988985 · DOI
  35. [39]Juergens RA Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer Cancer discovery 1 598 607 10.1158/2159-8290.CD-11-0214 2011 22586682 PMC3353724 · DOI
  36. [40]Kim K Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells Proceedings of the National Academy of Sciences of the United States of America 111 11774 11779 10.1073/pnas.1410626111 2014 25071169 PMC4136565 · DOI · Paper page
  37. [41]Schroeder T Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation Leukemia 27 1229 1235 10.1038/leu.2013.7 2013 23314834 · DOI
  38. [42]Steinmann J 5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft Bone marrow transplantation 50 690 695 10.1038/bmt.2015.10 2015 25774594 · DOI
  39. [44]Bhuvanagiri M 5-azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion EMBO molecular medicine 6 1593 1609 10.15252/emmm.201404461 2014 25319547 PMC4287977 · DOI
  40. [45]Setiadi AF Epigenetic enhancement of antigen processing and presentation promotes immune recognition of tumors Cancer research 68 9601 9607 10.1158/0008-5472.CAN-07-5270 2008 19047136 · DOI
  41. [46]Peng D Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy Nature 527 249 253 10.1038/nature15520 2015 26503055 PMC4779053 · DOI · Paper page
  42. [47]Almstedt M The DNA demethylating agent 5-aza-2′-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells Leukemia research 34 899 905 10.1016/j.leukres.2010.02.004 2010 20381863 · DOI
  43. [48]Anders S Huber W Differential expression analysis for sequence count data Genome biology 11 R106 10.1186/gb-2010-11-10-r106 2010 20979621 PMC3218662 · DOI · Paper page
  44. [49]Zhao M Kim P Mitra R Zhao J Zhao Z TSGene 2.0: an updated literature-based knowledgebase for tumor suppressor genes Nucleic acids research 10.1093/nar/gkv1268 2015 PMC4702895 26590405 · DOI
  45. [50]Heinz S Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities Molecular cell 38 576 589 10.1016/j.molcel.2010.05.004 2010 20513432 PMC2898526 · DOI · Paper page
  46. [51]Kong L CPC: assess the protein-coding potential of transcripts using sequence features and support vector machine Nucleic acids research 35 W345 349 10.1093/nar/gkm391 2007 17631615 PMC1933232 · DOI
  47. [52]Nielsen M NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence PloS one 2 e796 10.1371/journal.pone.0000796 2007 17726526 PMC1949492 · DOI
  48. [53]Zhao X Valen E Parker BJ Sandelin A Systematic clustering of transcription start site landscapes PloS one 6 e23409 10.1371/journal.pone.0023409 2011 21887249 PMC3160847 · DOI
  49. [54]Kim D Langmead B Salzberg SL HISAT: a fast spliced aligner with low memory requirements Nature methods 12 357 360 10.1038/nmeth.3317 2015 25751142 PMC4655817 · DOI · Paper page
  50. [55]Haberle V Forrest AR Hayashizaki Y Carninci P Lenhard B CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses Nucleic acids research 43 e51 10.1093/nar/gkv054 2015 25653163 PMC4417143 · DOI
  51. [56]Lawrence M Software for computing and annotating genomic ranges PLoS computational biology 9 e1003118 10.1371/journal.pcbi.1003118 2013 23950696 PMC3738458 · DOI
  52. [57]Robinson MD McCarthy DJ Smyth GK edgeR: a Bioconductor package for differential expression analysis of digital gene expression data Bioinformatics 26 139 140 10.1093/bioinformatics/btp616 2010 19910308 PMC2796818 · DOI · Paper page
  53. [58]Li H Durbin R Fast and accurate short read alignment with Burrows-Wheeler transform Bioinformatics 25 1754 1760 10.1093/bioinformatics/btp324 2009 19451168 PMC2705234 · DOI · Paper page
  54. [59]Zhang Y Model-based analysis of ChIP-Seq (MACS) Genome biology 9 R137 10.1186/gb-2008-9-9-r137 2008 18798982 PMC2592715 · DOI · Paper page
  55. [60]Lister R Human DNA methylomes at base resolution show widespread epigenomic differences Nature 462 315 322 10.1038/nature08514 2009 19829295 PMC2857523 · DOI · Paper page
  56. [61]Wang Q Tagmentation-based whole-genome bisulfite sequencing Nature protocols 8 2022 2032 10.1038/nprot.2013.118 2013 24071908 · DOI
  57. [62]Hansen KD Langmead B Irizarry RA BSmooth: from whole genome bisulfite sequencing reads to differentially methylated regions Genome biology 13 R83 10.1186/gb-2012-13-10-r83 2012 23034175 PMC3491411 · DOI
  58. [63]Rice P Longden I Bleasby A EMBOSS: the European Molecular Biology Open Software Suite Trends in genetics: TIG 16 276 277 2000 10827456
  59. [64]Claus R Quantitative analyses of DAPK1 methylation in AML and MDS International journal of cancer Journal international du cancer 131 E138 142 10.1002/ijc.26429 2012 21918973 PMC3463871 · DOI
  60. [65]Calvo SE Pagliarini DJ Mootha VK Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans Proceedings of the National Academy of Sciences of the United States of America 106 7507 7512 10.1073/pnas.0810916106 2009 19372376 PMC2669787 · DOI · Paper page
  61. [66]Kozak M An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNAs Nucleic acids research 15 8125 8148 1987 3313277 PMC306349
  62. [67]Jackson RJ Hellen CU Pestova TV The mechanism of eukaryotic translation initiation and principles of its regulation Nature reviews Molecular cell biology 11 113 127 10.1038/nrm2838 2010 20094052 PMC4461372 · DOI · Paper page
  63. [68]Grillo G UTRdb and UTRsite (RELEASE 2010): a collection of sequences and regulatory motifs of the untranslated regions of eukaryotic mRNAs Nucleic acids research 38 D75 80 10.1093/nar/gkp902 2010 19880380 PMC2808995 · DOI
  64. [69]Smith TF Waterman MS Identification of common molecular subsequences Journal of molecular biology 147 195 197 1981 7265238

Cited by

Sorted by citations

Authors
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., & Plass, C.
Affiliations
  • German Cancer Research Center (DE)
  • Washington University in St. Louis (US)
  • University of Freiburg (DE)
Corresponding author
  • Oakes, Christopher C
  • Wang, Ting
  • Plass, Christoph
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2017-06-12
Volume
49
Issue
7
Pages
1052-1060
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.3889
PMC
PMC6005702
OpenAlex
W2625655191
Cited by
339
References
5
Citations by year
2026: 24 · 2025: 31 · 2024: 34 · 2023: 30 · 2022: 47 · 2021: 44 · 2020: 43 · 2019: 40 · 2018: 33 · 2017: 12 · 2015: 1
FWCI
15.53
Type
journal article
Language
en
Update notices
erratum (2017-11-01)
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
Funders
  • National Institute on Drug Abuse (R25DA027995)
  • National Human Genome Research Institute (R01HG007175, U01HG009391, R01HG007354)
  • National Cancer Institute (U01CA200060)
  • National Institute of Environmental Health Sciences (R01ES024992, U24ES026699)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
DNMT inhibitors, histone deacetylase inhibitors, long terminal repeat, endogenous retroviruses, DNA hypomethylation, histone acetylation, H3K14ac, truncated transcripts, epigenetic reprogramming, cancer cell lines, transcriptome
MeSH terms
DNA (Cytosine-5-)-Methyltransferase 1, Vorinostat, Animals, Benzimidazoles, DNA (Cytosine-5-)-Methyltransferases, Exons, Female, Humans, Hydroxamic Acids, Introns, Mice, Nude, Recombinant Fusion Proteins, Alternative Splicing, DNA Methylation, Terminal Repeat Sequences, Gene Silencing, Gene Expression Profiling, Transcription Initiation Site, RNA Interference, Histone Code, Cell Line, Tumor, Mice, Histone Deacetylase Inhibitors, Epigenetic Repression, Death-Associated Protein Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review