Transposable elements (TEs) are an abundant and rich genetic resource of regulatory sequences 1 – 3 . Cryptic regulatory elements within TEs can be epigenetically reactivated in cancer to influence oncogenesis in a process termed onco-exaptation 4 . However, the prevalence and impact of TE onco-exaptation events across cancer types are poorly characterized. Here, we analyzed 7,769 tumors and 625 normal datasets from 15 cancer types, identifying 129 TE cryptic promoter activation events involving 106 oncogenes across 3,864 tumors. Furthermore, we interrogated the AluJb-LIN28B candidate: the genetic deletion of the TE eliminated oncogene expression, while dynamic DNA methylation modulated promoter activity, illustrating the necessity and sufficiency of a TE for oncogene activation. Collectively, our results characterize the global profile of TE onco-exaptation and highlight this prevalent phenomenon as an important mechanism for promiscuous oncogene activation and ultimately tumorigenesis.

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).

Background: Transposable elements (TEs) make up half of mammalian genomes and shape genome regulation by harboring binding sites for regulatory factors. These include binding sites for architectural proteins, such as CTCF, RAD21, and SMC3, that are involved in tethering chromatin loops and marking domain boundaries. The 3D organization of the mammalian genome is intimately linked to its function and is remarkably conserved. However, the mechanisms by which these structural intricacies emerge and evolve have not been thoroughly probed. Results: Here, we show that TEs contribute extensively to both the formation of species-specific loops in humans and mice through deposition of novel anchoring motifs, as well as to the maintenance of conserved loops across both species through CTCF binding site turnover. The latter function demonstrates the ability of TEs to contribute to genome plasticity and reinforce conserved genome architecture as redundant loop anchors. Deleting such candidate TEs in human cells leads to the collapse of conserved loop and domain structures. These TEs are also marked by reduced DNA methylation and bear mutational signatures of hypomethylation through evolutionary time. Conclusions: TEs have long been considered a source of genetic innovation. By examining their contribution to genome topology, we show that TEs can contribute to regulatory plasticity by inducing redundancy and potentiating genetic drift locally while conserving genome architecture globally, revealing a paradigm for defining regulatory conservation in the noncoding genome beyond classic sequence-level conservation.

BackgroundUncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes. While studies have confirmed DNA methylation as a conserved epigenetic mechanism in mammalian development, little is known about the conservation of tissue-specific genome-wide DNA methylation patterns.ResultsUsing a comparative epigenomics approach, we identified and compared the tissue-specific DNA methylation patterns of rat against those of mouse and human across three shared tissue types. We confirmed that tissue-specific differentially methylated regions are strongly associated with tissue-specific regulatory elements. Comparisons between species revealed that at a minimum 11-37% of tissue-specific DNA methylation patterns are conserved, a phenomenon that we define as epigenetic conservation. Conserved DNA methylation is accompanied by conservation of other epigenetic marks including histone modifications. Although a significant amount of locus-specific methylation is epigenetically conserved, the majority of tissue-specific DNA methylation is not conserved across the species and tissue types that we investigated. Examination of the genetic underpinning of epigenetic conservation suggests that primary sequence conservation is a driving force behind epigenetic conservation. In contrast, evolutionary dynamics of tissue-specific DNA methylation are best explained by the maintenance or turnover of binding sites for important transcription factors.ConclusionsOur study extends the limited literature of comparative epigenomics and suggests a new paradigm for epigenetic conservation without genetic conservation through analysis of transcription factor binding sites.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4115-6) contains supplementary material, which is available to authorized users.

Empirical models of sequence evolution have spurred progress in the field of evolutionary genetics for decades. We are now realizing the importance and complexity of the eukaryotic epigenome. While epigenome analysis has been applied to genomes from single cell eukaryotes to human, comparative analyses are still relatively few, and computational algorithms to quantify epigenome evolution remain scarce. Accordingly, a quantitative model of epigenome evolution remains to be established. Here we review the comparative epigenomics literature and synthesize its overarching themes. We also suggest one mechanism, transcription factor binding site turnover, which relates sequence evolution to epigenetic conservation or divergence. Lastly, we propose a framework for how the field can move forward to build a coherent quantitative model of epigenome evolution.