Drs. Andrew Fire and Craig Mello won this year’s Nobel Prize in Physiology or Medicine for their discovery of RNA interference. Their discoveries revealed fundamental new paradigm in gene regulation and demonstrated that animal genomes consist of not only the transcriptional programs controlled by transcription factors but also the post-transcriptional programs controlled by RNAs. MiRNAs are ~22-nt small regulatory RNAs that are thought to control gene expression at the post-transcriptional level by targeting cognate target mRNAs for either degradation or translational repression. MiRNAs are individually encoded by their own set of genes and represent an integral component of animal genetic programs. MiRNA genes constitute about 1-5% of the predicted genes in worms, mice, and humans, and many miRNAs are conserved from worm to human. Moreover, each miRNA has the potential to regulate as many as 200 target genes, which implies that miRNA-mediated gene regulation may have a broad impact on gene expression and likely represents a fundamental layer of the genetic programs at the post-transcriptional level. Not surprisingly, miRNAs have been shown to play important roles in regulating various cellular, developmental, and disease processes in worm, fly, mouse, and human and several lines of evidence have implicated miRNAs in the developmental regulatory decisions of stem-cell maintenance and differentiation in flies and mice. However, the roles of miRNAs in human embryonic stem cell maintenance and differentiation are still unknown. The proposed research plan will address the fundamental questions regarding the roles of miRNAs and miRNA-mediated posttranscriptional genetic programs in human embryonic stem cells.
To realize the clinical potential human embryonic stem cells, one has to understand the fundamental molecular mechanisms that govern stem cells self-renewal and differentiation. Human embryonic stem cells have a number of important properties: they can propagate under the right culture conditions and they can differentiate into cell types of all human tissues if properly guided. However, until today the molecular processes that regulate these properties are still quite elusive. The proposed research plan will address the fundamental molecular mechanisms that govern stem cells self-renewal and differentiation from a new angel –– the recently discovered post-transcriptional genetic programs controlled by small regulatory RNAs. Thus, these studies are likely to reveal important missing puzzle pieces that may be required for solving the ultimate question and yield clues to harness the power of human embryonic stem cells.