Project Details
Projekt
Molecular mechanisms of epigenetic therapies
Subject Area
Hematology, Oncology
Term
since 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 336840530
In contrast to genetic mutations, epigenetic changes are potentially reversible, which deems them an attractive target for cancer treatment. Inhibitors directed against DNA methyltransferases (DNMTi) as well as histone deacetylases (HDACi) are used in the clinic for the treatment of several hematopoietic malignancies. However, despite their clinical use for several years, there is still a lack of knowledge regarding the mechanistic basis for their clinical activity. DNA methyltransferase and histone deacetylase inhibitors promote the reversion of epigenetic states and are approved cancer therapies. While several mechanisms of action have been proposed, mainly based on candidate gene approaches, less is known about the genome-wide transcriptional and epigenomic consequences of treatment. By mapping global transcription start site (TSS) and chromatin dynamics after pharmacological inhibition of DNMTs and HDACs, we found that besides the reactivation of epigenetically silenced genes, the activation of 2,000 - 3,000 cryptic TSSs encoded in long-terminal repeats (LTR) of the LTR12 family was the major change following treatment. LTR activation by DNMT but not HDAC inhibition coincided with a shift from a repressed to a transcription-permissive chromatin state. Moreover, LTR-derived transcripts were spliced into downstream genic exons and the resulting chimeric transcripts encode truncated or novel open reading frames that are translated. Since these translation products are predicted to have aberrant and potentially immunogenic functions, the widespread activation of cryptic TSSs has implications for epigenetic-based therapies. Here we propose a research plan that will (i) help to shed light on the molecular mechanisms of synergistic effects of DNMTi and HDACi, (ii) will result in improved biomarkers, (iii) will uncover potential targets for immunotherapy and (iv) will help to improve the use of epigenetic drugs, either as single agent or in combination therapy in the clinic.
DFG Programme
Research Units
