Our laboratory is interested in determining the molecular mechanisms that regulate stem cell differentiation and de-differentiation and how these mechanisms become deregulated in cancer. Since starting the lab in 2006, we have been largely focusing on the role of post-transcriptional regulators including microRNAs (miRNAs) and RNA binding proteins (RBPs).
Embryonic Stem Cells
We have shown that a specific family of miRNAs, which we call the ESCC family, is a powerful inducer and stabilizer of the mammalian embryonic stem cell (ESC) fate. We found that this family suppresses hundreds of downstream mRNA targets. By following a subset of these targets, we now know that the ESCC miRNAs function in part by directing the unique cell cycle structure, the epithelial state, and the epigenetic state of ESCs. We are currently dissecting the role of all the ESCC miRNA downstream targets in pluripotency. In parallel, we have uncovered other miRNAs that have the opposite function to the ESCC miRNAs in that they promote differentiation. Indeed the differentiating miRNAs are antagonized by the ESCC miRNAs. We are dissecting the mechanisms of these miRNAs in ESC differentiation. Furthermore, we are studying the roles of the ESCC miRNAs in vivo. The ESCC miRNAs are expressed from two genetic loci. We are using genetic tools to understand their role in mammalian development.
Somatic Stem and Germ Cells
The lab is also studying the role of small RNAs in other stem cell types and in vivo developmental stages. In particular, we are studying miRNA roles in trophoblast stem cells, glial progenitor cells, and oocytes. We recently made the surprising finding that miRNA function is globally suppressed in mammalian oocytes. We are following up this finding by trying to understand how and why all miRNA function is temporarily inactivated during this critical developmental time window. Simultaneously, we discovered that another class of small RNAs, endogenous siRNA (endo-siRNAs) are essential for oocyte meiosis. We are currently dissecting the specific endo-siRNAs and targets responsible for meiotic progression.
Finally, we are studying the roles of miRNAs in cancer with a particular focus on prostate cancer. We have discovered that miRNAs are essential for the progression of prostate cancer from a hyperplastic to dysplastic lesion. Similar to our ESC work, we are using genomic approaches to uncover the miRNA-mRNA networks in order to dissect the molecular pathways required for progression. Furthermore, we have been analyzing miRNA signatures in the serum of prostate cancer patients, identifying miRNAs that prospectively identify patients at risk for progression and determine how they will respond to specific therapies.