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Tumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human  MAGEA6 / GABRA3  gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript ( CT-GABRA3 ) that overlaps downstream promoters ( GABRQ  and  GABRA3 ) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark deposited during transcriptional elongation and known to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the  CT-GABRA3  overlapping transcript. Importantly, experimental induction of  CT-GABRA3  by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of regional DNA hypermethylation. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo/hypermethylation, and some of these included tumor suppressor genes, e.g.  RERG  and  PTPRO . Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.

Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer