Richard Gregory, Ph.D.
Department of Biological Chemistry and Molecular Pharmacology
Karp 9th Floor
1 Blackfan Circle
Boston, MA 02115
Lab Members: 5 postdoctoral fellows, 1 graduate student
Mechanisms of microRNA biogenesis and function in stem cells, development, and disease
Our research program is focused on understanding posttranscriptional mechanisms controlling microRNA and messenger RNA expression and to explore the relevance of these pathways in stem cell pluripotency, mammalian development, and human disease. Embryonic stem cells (ESCs) have the remarkable capacity to self-renew and to differentiate into all cell types and are of potential therapeutic value for numerous degenerative diseases. However, the molecular foundations of stem cell maintenance and cellular pluripotency remain poorly defined. It is emerging that cells possess a wide repertoire of tiny regulatory RNAs that are critical for a variety of biological pathways and can repress genes via numerous mechanisms. For posttranscriptional gene silencing, microRNAs (miRNAs), and small inhibitory RNAs (siRNAs), function as guide molecules inducing mRNA degradation or translational repression. miRNAs in stem cell self-renewal and differentiation. We aim to exploit this understanding for the development of new therapeutic approaches for cancer and degenerative disease. Our identification of the pluripotency factor Lin28 as a selective inhibitor of miRNA biogenesis represents a clear example of how these fields converge (1). Indeed, a large part of our current research is focused on understanding the mechanism by which Lin28 and Lin28B control the processing of the let-7 family of miRNAs in stem cells and cancer, and importantly finding ways to manipulate this pathway for new therapies (1-3). Some of our ongoing and future work originates from studies of the Lin28/let-7 pathway yet aims to extend these novel findings to study more broadly the role of RNA oligouridylation by 3’ terminal uridylyl transferases (TUTases) and the downstream nucleases in the posttranscriptional control of gene expression. Also we are actively working on identifying new miRNA gene regulatory pathways and seek to understand how cell-signaling pathways impact the miRNA biogenesis machinery as well as finding additional novel miRNA regulators (4). In summary, our specialized research program bridges RNA biochemistry/molecular biology and stem cell research and promises to provide both fundamental mechanistic insight as well as new therapeutic opportunities for a variety of human diseases.
Viswanathan S. R., Daley G. Q., and Gregory R. I. (2008) Selective Blockade of MicroRNA Processing by Lin28. Science 320, 97-100.
Hagan J.P*., Piskounova E*, Gregory R. I. (2009) Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nat Struct Mol Biol. 16, 1021-5. (*equal contribution).
Piskounova E., Polytarchou C., Thornton J. E., Hagan J.P., LaPierre R. J., Pothoulakis C., Iliopoulos D., and Gregory R. I. (2011) Oncogenic Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell 2011, 147, 1066-79.
Chang H.*, Martinez N. J.*, Thornton J. E. and Gregory R. I. (2012) Trim71 cooperates with microRNAs to repress Cdkn1a expression and promote embryonic stem cell proliferation. Nature Communications, doi: 10.1038/ncomms1909. (* equal contribution).
For a complete listing of publications click here.
Last Update: 8/1/2012