Robert Blelloch, MD, PhD
Robert Blelloch, MD, PhD
Epigenetics, Stem Cells and Cancer
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.
Wang Y, Medvid R, Melton C, Jaenisch R, Blelloch R. DGCR8 is Essential for MicroRNA Biogenesis an Efficient Embryonic Stem Cell Differentiation. Nature Genetics, 2007: 39:380-5. Epub 2007 Jan 28.
Babiarz J, Ruby G, Wang Y, Bartel D, Blelloch R. Mouse ES Cells Express Endogenous shRNAs, siRNAs, and Other Microprocessor-independent, Dicer-dependent Small RNAs. Genes and Development, 2008: 22:2773-85.
Wang Y, Baskerville S, Shenoy A, Babiarz JE, Baehner L, Blelloch R. Embryonic Stem Cell Specific MicroRNAs Regulate the G1/S Transition and Promote Rapid Proliferation. Nature Genetics, 2008: 40:1478-83. Epub Nov 2. 2008
Judson RL, Babiarz JE, Venere M, Blelloch R. Embryonic stem cell-specific microRNAs promote induced pluripotency. Nature Biotechnology, 2009: 27:459-61 Epub April, 12, 2009.
Melton C, Judson R, Blelloch R. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature, 2010, 463: 621-6. Epub 2010 Jan 6.
Suh N, Baehner L, Moltzhan F, Melton C, Shenoy A, Chen, Blelloch R. MicroRNA function is globally suppressed in mouse oocytes and early embryos. Current Biology, 2010, 20: 271-277. Epub 2010 Jan 28.
Subramanyam D, Belair CD, Barry-Holson KQ, Lin H, Kogan SC, Passegue, E, Blelloch R. PML-RARα and Dnmt3a1 cooperate in vivo to promote acute promyelocytic leukemia. Cancer Res. 2010, 70: 8792-801. Epub 2010 Sep 21
Moltzahn F, Olshen AB, Baehner L, Peek A, Fong L, Stöppler H, Simko J, Hilton JF, Carroll P, Blelloch R. Microfluidic-based multiplex qRT-PCR identifies diagnostic and prognostic microRNA signatures in the sera of prostate cancer patients. Cancer Res. 2011, 71:550-60. Epub 2010 Nov 22
Subramanyam D, Lamouille S, Judson RL, Liu JY, Bucay N, Derynck R, Blelloch R. Multiple targets of miR-302 and miR-372 promote human induced pluripotency. Nature Biotechnology. 2011. 29:443-8. Epub 2011 Apr 13.
Babiarz JE, Hsu R, Melton C, Thomas M, Ullian EM, Blelloch R. A role for non-canconical microRNAs in the mammalian brain revealed by phenotypic differences in Dgcr8 versus Dicer1 knockouts and small RNA sequencing. RNA. 2011 Jun 28.