Carl D. Novina

Department of Pathology, Harvard Medical School
Cancer Immunology and AIDS, Dana Farber Cancer Institute
Dana Building, Room 1420B
44 Binney Street
Boston, MA 02115
Tel: (617) 582-7961
Fax: (617) 582-7962
Email: carl_novina@dfci.harvard.edu
Web: The Novina Lab Page

4 Postdoctoral Fellows, 1 Graduate Student

Small RNAs have been implicated in numerous processes including developmental transitions, chromosomal segregation, tumorigenesis, and diabetes. An abundant class of ~22 nucleotide, short non-coding RNAs called microRNAs (miRNAs) are predicted to target more than one third of human genes for silencing. Still, the mechanisms used by miRNAs to silence these genes are poorly understood. My laboratory combines hypothesis-driven, discovery-driven, and computation-driven approaches to identify endogenous small RNAs, their cognate mRNA targets, and the factors that are involved in gene silencing processes collectively called RNA interference (RNAi). To understand how miRNAs function, we developed the first cell-free, miRNA-directed translational repression reactions. Using these reactions, we defined one mechanism used by miRNAs to repress translation initiation and we are now using these reactions to define the factor requirements for miRNA-directed translational repression of target mRNAs. In a complementary approach, we also devised reverse genetic screening systems to discover mammalian genes required for RNAi. Candidate RNAi gene and small RNAs identified by these approaches will be used to characterize gene silencing pathways in lymphocytes.

MicroRNAs play important roles in lymphocyte-specific gene regulation, a fact highlighted by the recent evidence that disruption of miRNA gene expression correlates with formation of several cancers including many leukemias and lymphomas. In collaboration with other laboratories at the Dana-Farber Cancer Institute, we profiled miRNA expression in normal T cell ontogeny and in two leukemias: chronic myeloid leukemia (CML, a cancer of defective differentiation) and chronic lymphocytic leukemia (CLL, a cancer of defective apoptosis). We have identified miRNAs that are important for lineage commitment during the blast phase of CML and for apoptosis in CLL. Using antagomiRs (antisense oligonuceotides to miRNAs) to inhibit increased miRNAs and using lentiviruses to reconstitute decreased miRNAs ex vivo and in mice ‘humanized’ with leukemia patient bone marrows, we are testing the consequences of altering the expression of these miRNAs in normal cells and in cancers. These data could provide valuable information about susceptibility to particular cancers and, eventually, potential response to therapeutic interventions.

Papers & Publications:

Wang B, Yanez A, Novina CD. miRNA-repressed mRNAs contain 40S, but not 60S components. under review.

Moffett HF, and Novina, CD. A small RNA makes a Bic difference. Gen. Biol. 2007; 8: 221 (doi:10.1186/gb-2007-8-7-221).

Wang B, Love TM, Call, ME, Doench, JG, Novina CD. Recapitulation of short RNA-directed translational gene silencing, in vitro. Mol. Cell 2006; 22:553-560.

Chowdhury D, and Novina CD. RNAi and RNA-based regulation of immune system function. Adv. Immunol. 2005; 88: 267-292.

Stewart SA, Dykxhoorn DM, Palliser D, Mizuno H, Yu EY, An DS, Sabatini DM, Chen ISY, Hahn WC, Sharp PA, Weinberg RA, Novina CD. Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA 2003; 9: 493-501.