Genome-wide Exploration of miRNA-mediated Network Motifs

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MicroRNAs (miRNAs) are extremely small (21-23 nucleotide) RNAs that do not encode proteins but serve as important post-transcriptional regulators. Specifically, miRNAs target messenger RNAs to which they are perfectly complementary for degradation, and those to which they can base pair with internal mismatches for translational repression. It is widely believed that miRNAs are embedded in an extensive array of gene regulatory circuits, thereby playing essential roles in establishing and maintaining cellular functions during development and differentiation. However, direct evidence in support of this proposal is lacking. Given the importance of miRNAs in gene regulation, one key question is how miRNA biogenesis itself is regulated at the levels of transcription and processing. To date, little has been learned about transcriptional regulation of miRNA genes, mainly due to the lack of information about the precise location of miRNA promoters. Mapping the transcriptional regulatory elements that comprise miRNA promoters is critical for determining the sequence motifs present and the factors with which they interact to turn on and off miRNA synthesis. The goal of this research project is to (1) use high throughput methods to globally determine the transcription start sites of miRNA genes in human cells; and (2) to use computational strategies to identify the sequence elements and regulatory factors involved in miRNA transcriptional control. Therefore, this study will serve as an initial yet critical step towards dissecting the molecular mechanism underlying regulated miRNA expression, bringing us one step closer to fully understanding miRNA-mediated gene regulation at the network/system level. Broader Impacts: The proposed project provides unique training opportunities for undergraduate, graduate and postdoctoral fellows in genome science, including but not limited to genome technology development and computational biology. In addition, the research program will promote curriculum development for graduate and undergraduate courses with an emphasis on genome biology. By taking advantage of the existing infrastructure and outreach programs at Duke University, in particular at the Institute for Genome Sciences & Policy and its associated NIGMS National Center for Systems Biology, the project will reach out to scientists of diverse backgrounds as well as educate the general public.