Epigenetic microRNA Regulation

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandlingForskning

  • Erik Digman Wiklund, Danmark
  • Molekylærbiologisk Institut
MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that negatively regulate gene expression post-transcriptionally by binding to complementary sequences in the 3’UTR of target mRNAs in the cytoplasm. However, recent evidence suggests that certain miRNAs are enriched in the nucleus, and their targets do not seem restricted to mRNA 3’UTRs. Therefore, miRNAs are predicted to have a variety functions throughout mammalian cells. MiRNA genes appear to be regulated in much the same way as coding genes, but current insight into transcriptional miRNA control lacks detail, as mapping miRNA promoters and confirming transcriptional start sites can be difficult. Epigenetics, gene regulatory and DNA modification mechanisms not involving a change to the primary sequence, have been implied in the regulation of a number of miRNA loci. Both epigenetic and miRNA signatures are broadly altered in cancer, and are thought to play essential roles in cancer etiology and progression. Here, we aimed to identify epigenetic miRNA deregulation in bladder and oral carcinoma, and to develop a robust approach to epigenetic miRNA prediction and detection. In addition, non-canonical epigenetic functions directed by a nuclear miRNA were investigated. In summary, we report that the miR-200 family and miR-205 are coordinately epigenetically regulated in a variety of cell lines, tumors and normal tissues. MiR-200c expression is correlated with bladder cancer disease progression, and miR-375 levels in oral rinse can distinguish oral cancer patients from healthy controls; these miRNAs therefore have potential applications as clinical biomarkers. Finally, we show that the predominantly nuclear miR-671 controls CDR1 expression via a novel regulatory mechanism involving a circular antisense RNA. The nuclear function of miR-671 appears to extend beyond CDR1 regulation, pointing to broader non-canonical roles for miRNAs in the nucleus of mammalian cells.
OriginalsprogEngelsk
StatusUdgivet - 2011

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