Epigenome modifier drugs triggeer widespread transcription of endogenous retroviruses

As these GEITP emails have often covered, phenotypes (or ‘traits’) –– such as individual differences in height, serum cholesterol levels, schizophrenia, cancer, drug efficacy, or toxicity due to a drug or environmental toxicant –– can reflect DNA sequence variants, epigenetic factors, and/or environmental effects. Moreover, epigenetic factors include DNA methylation, all forms of RNA-interference, histone modification, and chromatin remodeling.

The attached full-length paper and editorial describe factors that can play a role in regulating chro­matin structure and function, including the enzymes that modify histones or DNA. Of clinical relevance is that “epigenetic drugs” are now being used to treat a variety of severe diseases, including numerous cancer types. Although histones of cancer cells characteristically are globally hypomethylated (decreased numbers of methyl groups), CpG-island (CGI) promoters of tumor-suppressor genes (TSGs) are frequently hypermethylated (increased numbers of methyl groups) in many cancers. This finding has drawn the attention of oncologists to DNA-methylation inhibitor (DNMTi) drugs that have shown clinical efficacy for hematopoietic (blood) and certain solid tumors.

Authors of the full-length paper [attached] used “cap analysis of gene expression” (CAGE) to profile the distribution of de novo transcrip­tion start sites (TSSs) following treatment of a lung cancer cell line with the DNMTi 5-aza-2′-deoxycytidine (DAC) drug and/or the HDACi SB939 drug. Cancer testis antigens and viral defense genes were clearly up-regulated, as shown previously for DNMTi treatment. However, for all treatments, this up-regulation was observed predominantly from overlapping sets of non-annotated TSSs –– referred to by the authors as treatment-induced non-an­notated TSSs, or TINATs, rather than from known gene TSSs. Furthermore, combina­tion treatment resulted in a synergistic effect on TINAT activity. TINAT promot­ers were hypermethylated in untreated cells, but lost DNA methylation and gained active histone marks following DNMTi and HDACi treatment –– indicating that these promoters are activated as a direct consequence of the loss of DNA methylation.

Authors then focused on the coding poten­tial and regulatory regions of these novel tran­scription units. Amazingly, genomic mapping of TINATS showed that more than 80% overlapped with trans­posable elements. The long terminal repeats (LTRs) of ancient endogenous retroviruses –– which are normally silenced by DNA methylation in somatic cells –– were particularly enriched in TINATs. These data indicate that such LTRs are derepressed (i.e. becoming up-regulated) following DNMTi-induced hypomethylation; this has been observed previously for human teratocarcinoma cells treated with a DNMTi and in mouse erythroleukemia cells, suggesting that LTRs may generally be sensitive to this combination of epigenetic drugs.

This incredible finding (but some of us are not surprised by this effect of epigenetic drugs) indicates that epigenome-modifying drugs, used in cancer chemotherapy, are able to induce transcription from thousands of previously unannotated transcription start sites –– most of which are derived from ancient endogenous retroviruses that normally sit “quietly” in our genome. This mind-blowing finding, strengthened by previous related studies, suggests that induction of endogenous retroviruses, rather than direct effects on specific genes, may have a central role in cellular responses to such cancer chemotherapeutic agents and, in turn, their therapeutic efficacy. Therefore, this represents yet-another level of COMPLEXITY if anyone wishes to attempt to predict a patient’s individual response to a drug.

Nature Genet July 2017; 49: 1052–1060 [article] & pp 974–975 [News’n’Views]

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