Epigenetic regulation of miRNA genes in cancer genomes

CLL is the most common leukemia in the Western world. However, molecular aspects of pathogenesis are not completely understood to date.

Dysregulation of microRNAs (miRNAs) has been shown to contribute to CLL pathogenesis. Initial evidence came from the discovery of miR-15a and miR-16-1 in patients harboring the deletion 13q14 in CLL. Since then, several expression studies in CLL patients have revealed novel candidate miRNAs with strong aberrant expression compared to healthy individuals. We could demonstrate in addition that distinct DNA methylation patterns are associated with altered miRNA transcription in CLL patients.

Thus, we hypothesize that miRNA dysregulation in CLL broadly involves epigenetic mechanisms, in particular DNA methylation, and that these aberrant epigenetic events occur at distinct loci relevant for transcriptional control.

To elucidate the role of epigenetics in miRNA transcriptional regulation, genome-wide epigenetic profiling of miRNA loci (for DNA methylation and informative histone marks) will be performed on CLL patient samples using custom tiling array technology. This allows us to investigate simultaneously all annotated miRNAs including characterizations of their putative transcriptional start sites. Identified candidates will be validated for epigenetic changes and associated expression alterations, correlated with clinical features and subsequently functionally characterized for their mechanistic role in CLL pathogenesis.

Publications:

• Baer et al., Extensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia. Cancer Res. 2012
• Baer et al., Genome-wide epigenetic regulation of miRNAs in cancer. Cancer Res. 2013
• Baer et al., Epigenetic silencing of miR-708 enhances NF-κB signaling in chronic lymphocytic leukemia. Int. J. Cancer 2015