LTR12 promoter activation in a broad range of human tumor cells by HDAC inhibition

Krönung, Sonja Katharina; Beyer, Ulrike; Chiaramonte, Maria Luisa; Dolfini, Diletta; Mantovani, Roberto; Dobbelstein, Matthias

doi:10.18632/oncotarget.9255

Cited by 34 publications

(24 citation statements)

References 64 publications

(80 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with the reported recruitment of GATA2 to LTR12 elements 30 , we show that GATA2 is required for full LTR12C expression. The selectivity of HDACi towards the activation of LTR12 family elements was also reported for multiple other cancer types based on candidate gene approaches 31,32 , indicating that this is a universal mechanism. However, non-epigenetic treatment examples of EVR9/LTR12 reactivation have been discovered in viral-induced tumors 20 and in primary T cells infected with HIV 33 .…”

Section: Discussionmentioning

confidence: 56%

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

et al. 2017

View full text Add to dashboard Cite

Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi); mainly 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/or HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric open reading frames translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi coincided with DNA hypomethylation and gain in 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 since we found TINATs to be encoded in solitary long-terminal repeats of the LTR12 family, epigenetically repressed in virtually all normal cells. In contrast to genetic mutations, epigenetic changes are potentially reversible, which is deeming them an attractive target for cancer treatment. Inhibitors directed against DNA methyltransferases (DNMTi) and histone deacetylases (HDACi) are used for the treatment of several haematopoietic malignancies1,2. However, despite their clinical use for several years, there is still a lack of knowledge regarding the mode of action3. Two previous studies on DNMTi in cancer cell lines reported the up-regulation of double stranded RNA (dsRNA) molecules originating from codogenic endogenous retroviruses (ERV) followed by an interferon response and the induction of viral defense genes4,5. However, it remains unclear how other classes of epigenetic drugs integrate into these findings and whether there are additional effects, potentially missed by candidate gene approaches. Here, we globally mapped DNMTi and HDACi-induced transcriptomic and epigenomic changes by using whole-genome profiling technologies (Supplementary Fig. 1 and Supplementary Table 1) and show that the vast majority of TSSs that transcriptionally responded towards epigenetic modulation were cryptic, currently non-annotated TSSs encoded in solitary long-terminal repeats (LTRs).

show abstract

Section: Discussionmentioning

confidence: 56%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…IRF7 7 ) (Fig 4F). To our surprise, NFY, a known activator of LTR12C expression 20 , was positively associated with expression of cluster 2 loci while lacking association with the other group in HCT116 cells.…”

Section: Trans and Cis Factors Shape The Complex De-repression Landsccontrasting

confidence: 59%

Single cell analysis reveals dynamics of transposable element transcription following epigenetic de-repression

Brocks

Chomsky

Mukamel

et al. 2018

Preprint

View full text Add to dashboard Cite

Spontaneous or pharmacological loss of epigenetic repression exposes thousands of promoters encoded in transposable elements (TEs) for pervasive transcriptional activation. How TE responses differ between epigenetically relaxed cancer cells and what factors govern such variation remains however largely unknown. By quantifying TE transcription initiation at single cell and locus resolution in epigenetically targeted cancer cells, we characterize specific groups of co-regulated loci that drive over ten-fold variation in TE load per single cell. Such variable activity patterns are largely linked to cell cycle stages, stress response signatures, and immune pathways. Furthermore, cells with high levels of specific transcription factors show increased TE expression, while within such cells, multi-copy families are differentially regulated in response to local sequence divergence of binding sites and the locus' repressive or active chromosomal contexts. Our data thereby implicates the regulation of potent promoters within TEs as an underestimated source of transcriptional heterogeneity following epigenetic therapy.

show abstract

“…Furthermore, treatment of uninfected and HIV-infected primary CD4 + T cells with another HDAC inhibitor, panobinostat (20 nM), for 24 h did not result in the upregulation of these HERV genes. In contrast, Kronung et al ( 20 ) previously applied another targeted RT-qPCR approach to study the expression of transcripts of the TP63 and TNFRSF10B genes that are under control of an LTR12 promoter derived from the HERV-9 family. Treatment with vorinostat (1 or 5 µM) for 18 h upregulated these genes via the LTR12 promoter across various cells lines (i.e., GH, H1299, K562, U2OS, HeLa, Ovcar-3, and HuT-78) suggesting that this drug may indeed modulate HERV elements.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Modulation of Human Endogenous Retroviruses in Primary CD4+ T Cells Following Vorinostat Treatment

et al. 2018

View full text Add to dashboard Cite

The greatest obstacle to a cure for HIV is the provirus that integrates into the genome of the infected cell and persists despite antiretroviral therapy. A “shock and kill” approach has been proposed as a strategy for an HIV cure whereby drugs and compounds referred to as latency-reversing agents (LRAs) are used to “shock” the silent provirus into active replication to permit “killing” by virus-induced pathology or immune recognition. The LRA most utilized to date in clinical trials has been the histone deacetylase (HDAC) inhibitor—vorinostat. Potentially, pathological off-target effects of vorinostat may result from the activation of human endogenous retroviruses (HERVs), which share common ancestry with exogenous retroviruses including HIV. To explore the effects of HDAC inhibition on HERV transcription, an unbiased pharmacogenomics approach (total RNA-Seq) was used to evaluate HERV expression following the exposure of primary CD4+ T cells to a high dose of vorinostat. Over 2,000 individual HERV elements were found to be significantly modulated by vorinostat, whereby elements belonging to the ERVL family (e.g., LTR16C and LTR33) were predominantly downregulated, in contrast to LTR12 elements of the HERV-9 family, which exhibited the greatest signal, with the upregulation of 140 distinct elements. The modulation of three different LTR12 elements by vorinostat was confirmed by droplet digital PCR along a dose–response curve. The monitoring of LTR12 expression during clinical trials with vorinostat may be indicated to assess the impact of this HERV on the human genome and host immunity.

show abstract

LTR12 promoter activation in a broad range of human tumor cells by HDAC inhibition

Cited by 34 publications

References 64 publications

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

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

Single cell analysis reveals dynamics of transposable element transcription following epigenetic de-repression

Transcriptional Modulation of Human Endogenous Retroviruses in Primary CD4+ T Cells Following Vorinostat Treatment

Contact Info

Product

Resources

About