Contemporary biology has been revolutionized by a recently discovered class of small regulatory RNA molecules-microRNAs (miRNAs). Missed by researchers for decades owing to their tiny size, usually mapping to non-protein-coding regions of genomes, miRNAs and miRNA-mediated regulatory networks have been the "dark matter" of molecular biology. The discovery of hundreds tiny RNA molecules expressed in a variety of organisms across phylogeny, including mammals, has opened an entirely novel way to understand gene regulation and manipulate their function.
miRNAs are non-protein-coding RNA molecules of just 18-25 nucleotides, that regulate gene expression by targeting the messenger RNA (mRNA) of at least 20% of human protein-coding genes for either cleavage or repression of translation. They regulate diverse biological processes, and computational predictions indicate that each miRNA can regulate hundreds of protein targets, underscoring the potential influence of miRNAs on almost every genetic pathway and biochemical process. Although most of mRNA targets have not yet been validated for the approximately 1000 known mammalian miRNAs, they can clearly form extensive regulatory networks with a complexity comparable to that of the transcription factors.
Our lab is interested in miRNA regulation of brain function and miRNA contribution in human brain diseases. At least several hundred miRNA molecules are present in mammalian brain. Their amount varies from single molecule up to ~10,000 molecules per cell. Many of them are predominantly expressed in developing or mature brain and demonstrate distinct expression patterns during mammalian brain development. Such patterns also suggested a role in neural differentiation. In line with these observations, we have described the miRNA expression profiles in mouse embryonic stem cell (ESC) -derived neurogenesis in culture. Remarkably, there is a clear correlation between such miRNAs profiles during neuronal development in culture and brain development in vivo. We have further demonstrated that brain specific miRNA molecules miR-124a and miR-9 affect neuronal and glial lineage differentiation in the ESC-derived cultures.
Roles of miRNAs in determination of neural cell fates as well as location of several miRNA genes at genomic regions linked to human cancers led to a hypothesis that miRNAs could be important factors in development or maintenance of neoplastic state, particularly- of brain malignancies. Using oligonucleotide chip for high-throughput analysis of miRNA expression and other technologies developed in our laboratory, we study miRNAs dysregulated in brain malignancies and neurologic diseases. For example, analysis of miRNA expression in glioblastoma, human most common and malignant brain tumor, revealed a clear "signature"of miRNAs that are dysregulated. Some of them are significantly reduced in gliomas; perhaps their normal expression is required for a tumor suppression function. There are also miRNAs elevated in gliomas that may potentially serve a role of oncogenes.
One interesting example is miR-21. This miRNA is strongly over-expressed in glioblastoma and it's also one of a few that are elevated in a variety of other solid cancers, including breast, lung, colon, prostate, pancreas and stomach cancers. These data suggest an important function for miR-21 in carcinogenesis. We are trying to identify miR-21 targets and signaling pathways involved in glioma progression. We believe that regulatory microRNA molecules can serve as prognostic markers and therapeutic targets for the treatment of brain tumors and probably other CNS disorders.
Harvard Medical School, Center for Neurologic Diseases
Brigham & Women's Hospital, Boston, MA
