Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program.
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).
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