Characterisation of cis-regulatory variations that dysregulate driver microRNAs in cancer

MicroRNAs (miRNAs) are a class of ∼21nt-long RNAs involved in translation regulation controlling key cellular processes such as cell differentiation, growth, mobility, and apoptosis. Despite our knowledge on miRNA locations in the human genome, the grasp on their transcriptional regulation is limited. With miRNAs known to be involved in cancer initiation and progression, a better understanding of miRNA transcriptional regulation and its disruption in cancer is required.

Transcription factors (TFs) and their DNA binding sites (TFBSs) act to modulate the rate of gene transcription. With increasing knowledge of regulatory regions associated with miRNA genes, we plan to predict which TFBSs and TFs are regulating these genes. These predictions will help us prioritize specific cis-regulatory variants (CRVs) disrupting cancer driver miRNA expression through TFBS alterations.

Inherent to delineating CRVs is the need to improve TFBS and TF target predictions. The availability of computational models and a wealth of experimental data dedicated to the identification TF-DNA interactions empowers our efforts to predict the specific locations of TFBSs by fusing computational and experimental approaches. In conjunction, we will implement new computational approaches for the prediction of TF targets and the underlying functional TFBSs. These predictions will enable us to predict the CRVs dysregulating miRNA transcription and contributing to cancer development in patients. In the proposed project, my group will develop novel computational resources, methods, and tools for improving TFBS predictions, predicting functional TFBSs associated to miRNA regulation, and prioritizing CRVs dysregulating driver miRNAs in cancer. Further, we will perform experimental validation to test the involvement of candidate driver miRNAs in cancer development. This work will further our understanding of miRNA gene expression regulation and will prioritize patient CRVs altering driver miRNAs in cancer.