Research Department

Cancer Immunology and AIDS

Area of Research

Biography

Dr. Novina received his PhD in 1998 from Tufts University, Sackler School of Graduate Biomedical Sciences, and his MD in 2000 from Columbia University, College of Physicians and Surgeons. He was a postdoctoral fellow in the laboratory of Dr. Phillip Sharp at Massachusetts Institute of Technology. He joined DFCI in 2004.

Research

Our interest in the function of short RNAs grew out of one of the most important advances in biology in the past decade: RNA interference (RNAi), a natural phenomenon that uses short, double-strand RNAs to silence genes. RNAi, which is widely conserved across phyla, is a method of genome defense in lower eukaryotes. While biological roles for short RNAs have been identified in other eukaryotes, their role in mammals is not clear. Short RNAs have been implicated in numerous processes including developmental transitions, chromosomal segregation, tumorigenesis, and diabetes, to name a few.

We are using several methods to identify mammalian short RNAs, their cognate mRNA targets, and the factors involved in gene silencing. While short RNA-directed cleavage of mRNA transcripts has been reported previously, reconstitution of the gene silencing reaction of short RNA-directed translation has never been reported in vitro; therefore, we are beginning to understand the reaction conditions and factor requirements for gene silencing in vitro. At the same time, we are testing RNAi factor requirements in cell-based assays using "virtual mutagens": libraries of genetic suppressor elements, small molecules (chemical), and short RNAs that dominantly inhibit gene silencing processes.

In addition, an abundant class of endogenous short noncoding RNAs, called microRNAs (miRNAs), are predicted to target more than one third of human genes. Though most mRNA targets of miRNAs are unknown, miRNAs 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. We have begun to identify miRNAs expressed in hematopoietic cells and their mRNA targets. Because identification of miRNA targets is complicated by imperfect nucleotide base-pairing between the miRNA and the mRNA, we also use bioinformatics to predict target mRNAs for miRNAs cloned from B and T cells. We can interrogate the consequences of miRNA-mRNA interaction in B and T cells by disrupting miRNA gene targeting function in a sequence-specific fashion.

Characterizing miRNA function in normal and transformed cells could provide valuable information about the processes naturally regulated by endogenous short RNAs, susceptibility to particular cancers, and - eventually - potential response to therapeutic interventions.

Select Publications

• Chowdhury D, Novina CD. RNAi and RNA-based regulation of immune system function. Adv Immunol 2005;88:267-92.
• Novina CD, Sharp PA. The RNAi revolution. Nature 2004;430:161-4.
• Song E, Lee S-K, Dykxhoorn DM, Novina C, Zhang D, Crawford K, Cerny J, Sharp PA, Lieberman J, Manjunath N, Shankar P. Sustained small interfering RNA-mediated human immunodeficiency virus type 1 inhibition in primary macrophages. J Virol 2003;77:7174-81.
  
• 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.
• Oka T, Vasile E, Penman M, Novina CD, Dykxhoorn DM, Ungar D, Hughson FM, Krieger M. Genetic analysis of the subunit organization and function of the conserved oligomeric Golgi (COG) complex: studies of COG5- and COG7-deficient mammlian cells. J Biol Chem 2005;280:32736-45.
• Chowdhury D, Novina CD. Potential roles for short RNAs in lymphocytes. Immunol Cell Biol 2005:83:201-10.
• Fan Z, Beresford PJ, Zhang D, Xu Z, Novina CD, Yoshida A, Pommier Y, Lieberman J. Cleaving the oxidative repair protein Apel enhances cell death mediated by granzyme A. Nat Immunol 2003;4:145-53.

Trainees

• Li, Shuqiang, PhD
• Love, Tara, PhD
• Wang, Bingbing, PhD