Richard Gregory, Ph.D.
Department of Biological Chemistry and Molecular Pharmacology
Children's Hospital
Karp Building, 9th Floor
1 Blackfan Circle
Boston, MA 02115
Tel: 617-919-2273
Fax: 617-730-0222
Email: rgregory@enders.tch.harvard.edu
4 postdoctoral fellows, 2 graduate students
Our research focus is to understand the mechanism and function of small regulatory RNAs in embryonic stem (ES) cells. ES cells 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 recently identified the developmentally regulated RNA-binding protein Lin28 as a selective inhibitor of miRNA processing in ES cells. Currently we are performing a detailed investigation into the mechanism by which Lin28 blocks miRNA processing, and exploring the relevance of this newly identified gene regulatory pathway in stem cell self-renewal and pluripotency. Additionally, we are performing high throughput chemical screens to identify specific inhibitors of the Microprocessor complex. We hypothesize that these chemicals will enable us to expand stem cell populations by preventing miRNA-mediated cell differentiation.
PiRNAs: a new class of small non-coding RNA molecules
Members of the Argonaute family of proteins play a central role in "RNA silencing" pathways that regulate transcription, heterochromatin, genome integrity, and mRNA stability. Argonaute proteins are divided into two subfamilies, Ago and Piwi. Ago members are ubiquitously expressed and are required for miRNA function. The expression of the members of the Piwi sub-family is restricted to stem cells and germ cells. Recently, a novel class of abundant small RNAs known as Piwi-interacting RNAs (piRNAs) was identified. This exciting discovery raises several fundamental questions of significant biological and biomedical relevance; what is the function of piRNAs? How are piRNAs generated? What is the identity of Piwi-interacting proteins? Although piRNA biogenesis and function is not yet well understood, Piwi proteins are highly expressed during mouse spermatogenesis and are important for gamete formation. We hypothesize that Piwi proteins and associated small RNAs have additional stem cell functions in mammals. We therefore aim to biochemically define the composition of Piwi-containing ribonucleoprotein complexes in human and mouse stem cells, towards our goal of understanding the mechanism of piRNA biogenesis, the function of the Piwi-complexes, and their requirement for stem cell biology.
References:
- Viswanathan S. R., Daley G. Q., and Gregory R. I. (2008) Selective Blockade of MicroRNA Processing by Lin28. Science 320, 97-100.
- Gregory R. I., Chendrimada T., Cooch N., and Shiekhattar R. (2005) Human RISC couples microRNA maturation and posttranscriptional gene silencing. Cell 123, 631-40.
- Chendrimada T.*, Gregory R. I.*, Kumaraswamy E.*, Norman J., Cooch N., Nishikura K., and Shiekhattar R. (2005) TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436, 740-4. (*equal contribution).
- Gregory R. I.*, Yan K.*, Amuthan G., Chendrimada T., Doratotaj B., Cooch N. and Shiekhattar R. (2004) The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235-240. (*equal contribution).
- 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).
For a complete listing of publications on PubMed, click here.
BBS webpage updated 6/14/2010