Photo of Carl Novina,  MD, PhD

Carl Novina, MD, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 582-7961
Fax: (617) 582-7962


carl_novina@dfci.harvard.edu

Carl Novina, MD, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Associate Professor, Microbiology and Immunobiology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

My lab is driven by two fundamental questions: (1) what is the mechanism by which microRNAs affect gene expression and (2) how does dysregulation of microRNA pathways influence oncogenesis? We described the first cell-free microRNA-mediated translation repression system which provided us with a unique tool to dissect the requirements for microRNA activity such as the requirement for target mRNAs to possess a physiological 7mG cap and thus showed that microRNAs can block translation initiation.

Using reverse genetic screening approaches we also showed that ribosomal protein genes (RPGs) as a class globally regulated microRNA-mediated repression of translation initiation. Reduced expression of any ribosomal protein selectively increased translation of microRNA-targeted mRNAs. This observation also led us to study a rare group of genetic diseases called ribosomopathies, characterized by reduced ribosome biogenesis and function, which include Diamond Blackfan Anemia (DBA) and Shwachman Diamond Syndrome (SDS). Clinically, these patients present with congenital anomalies, bone marrow failure (lineage-specific and pan-anemia) and cancer predisposition. It has been a long-standing mystery why patients present with this constellation of clinical findings. Because microRNAs frequently target body patterning genes, differentiation and developmental genes and oncogenes, we may have identified the molecular pathogenesis of ribosomopathies. We are currently using single cell RNA-seq of DBA- and SDS-patient bone marrow samples to investigate the mechanism by which reduced expression of ribosomal genes can promote cancers. Notably, an increasing number of cancers are characterized by reduced RPG expression. We are also investigating potential tumor suppressor roles for RPGs in a variety of cancers using combined biochemical and genomic approaches.

We are also investigating transcriptional regulation of microRNAs. Altered microRNA expression has been correlated with the tissue of origin, prognosis, and drug sensitivity of cancers and other diseases. Thus, it is critical to understand how microRNA expression is controlled in normal and disease contexts. MicroRNA expression is regulated by DNA methylation, as many microRNA genes exhibit aberrant promoter hypo- and hyper-methylation in cancer. To study the causes and consequences of inappropriate DNA methylation of microRNA genes, my lab is developing “epigenetic engineering” tools that will enable site-specific addition and removal of methyl groups on DNA. In contrast to genetically altering, sterically blocking, or transcriptionally activating target genes, epigenetically reprogramming target genes by site-specific DNA methylation or demethylation will lead to durable repression or activation, not requiring continuous expression of ectopic proteins.

We believe that epigenetic reprogramming of any gene of interest may be the next frontier in gene therapy. We are focused on targeted reprogramming of microRNA promoters and collaborate with other DFHCC members on epigenetic engineering of ovarian cancer genes (Dr. Drapkin), tumor-targeting immune cells or tumor-supporting stromal cells (Dr. Wucherpfennig), and putative tumor suppressor genes (Dr. Benjamin).

 

Publications

Powered by Harvard Catalyst
  • Mansour MR, Sanda T, Lawton LN, Li X, Kreslavsky T, Novina CD, Brand M, Gutierrez A, Kelliher MA, Jamieson CH, von Boehmer H, Young RA, Look AT. The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia. J Exp Med 2013; 210:1545-57. PubMed
  • Joyce CE, Novina CD. miR-155 in Acute Myeloid Leukemia: Not Merely a Prognostic Marker? J Clin Oncol 2013. PubMed
  • Horman SR, Janas MM, Litterst C, Wang B, Macrae IJ, Sever MJ, Morrissey DV, Graves P, Luo B, Umesalma S, Qi HH, Miraglia LJ, Novina CD, Orth AP. Akt-Mediated Phosphorylation of Argonaute 2 Downregulates Cleavage and Upregulates Translational Repression of MicroRNA Targets. Mol Cell 2013. PubMed
  • Janas MM, Wang B, Harris AS, Aguiar M, Shaffer JM, Subrahmanyam YV, Behlke MA, Wucherpfennig KW, Gygi SP, Gagnon E, Novina CD. Alternative RISC assembly: Binding and repression of microRNA-mRNA duplexes by human Ago proteins. RNA 2012; 18:2041-55. PubMed
  • Li X, Sanda T, Look AT, Novina CD, von Boehmer H. Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL. J Exp Med 2011. PubMed
  • Li S, Moffett HF, Lu J, Werner L, Zhang H, Ritz J, Neuberg D, Wucherpfennig KW, Brown JR, Novina CD. MicroRNA Expression Profiling Identifies Activated B Cell Status in Chronic Lymphocytic Leukemia Cells. PLoS ONE 2011; 6:e16956. PubMed
  • Levy C, Khaled M, Iliopoulos D, Janas MM, Schubert S, Pinner S, Chen PH, Li S, Fletcher AL, Yokoyama S, Scott KL, Garraway LA, Song JS, Granter SR, Turley SJ, Fisher DE, Novina CD. Intronic miR-211 Assumes the Tumor Suppressive Function of Its Host Gene in Melanoma. Mol Cell 2010; 40:841-849. PubMed
  • Wang B, Li S, Qi HH, Chowdhury D, Shi Y, Novina CD. Distinct passenger strand and mRNA cleavage activities of human Argonaute proteins. Nat Struct Mol Biol 2009; 16:1259-66. PubMed
  • Omer AD, Janas MM, Novina CD. The chicken or the egg: microRNA-mediated regulation of mRNA translation or mRNA stability. Mol Cell 2009; 35:739-40. PubMed
  • Roccaro AM,Sacco A,Chen C,Runnels J,Leleu X,Azab F,Azab AK,Jia X,Ngo HT,Melhem MR,Burwick N,Varticovski L,Novina CD,Rollins BJ,Anderson KC,Ghobrial IM. microRNA expression in the biology, prognosis, and therapy of Waldenstrom macroglobulinemia. Blood 2008; 113:4391-402. PubMed
  • Cosmopoulos K,Pegtel M,Hawkins J,Moffett H,Novina C,Middeldorp J,Thorley-Lawson DA. Comprehensive profiling of Epstein-Barr virus microRNAs in nasopharyngeal carcinoma. J Virol 2008; 83:2357-67. PubMed
  • Wang B, Yanez A, Novina CD. MicroRNA-repressed mRNAs contain 40S but not 60S components. Proc Natl Acad Sci U S A 2008; 105:5343-8. PubMed
  • Love TM, Moffett HF, Novina CD. Not miR-ly small RNAs: big potential for microRNAs in therapy. J Allergy Clin Immunol 2008; 121:309-19. PubMed
  • Novina CD, Chabner BA. RNA-Directed Therapy: The Next Step in the miRNA Revolution. Oncologist 2008; 13:1-3. PubMed
  • Wang B, Doench JG, Novina CD. Analysis of microRNA effector functions in vitro. Methods 2007; 43:91-104. PubMed
  • Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 2007; 117:112-21. PubMed
  • Hakre S, Tussie-Luna MI, Ashworth T, Novina CD, Settleman J, Sharp PA, Roy AL. Opposing functions of TFII-I spliced isoforms in growth factor-induced gene expression. Mol Cell 2006; 24:301-8. PubMed
  • Wang B, Love TM, Call ME, Doench JG, Novina CD. Recapitulation of short RNA-directed translational gene silencing in vitro. Mol Cell 2006; 22:553-60. PubMed
  • 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 mammalian cells. J Biol Chem 2005; 280:32736-45. PubMed
  • Chowdhury D, Novina CD. Potential roles for short RNAs in lymphocytes. Immunol Cell Biol 2005; 83:201-10. PubMed
  • Novina CD, Sharp PA. The RNAi revolution. Nature 2004; 430:161-4. PubMed
  • Song E, Lee SK, 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. PubMed
  • Stewart SA, Dykxhoorn DM, Palliser D, Mizuno H, Yu EY, An DS, Sabatini DM, Chen IS, Hahn WC, Sharp PA, Weinberg RA, Novina CD. Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA 2003; 9:493-501. PubMed
  • Novina CD, Murray MF, Dykxhoorn DM, Beresford PJ, Riess J, Lee SK, Collman RG, Lieberman J, Shankar P, Sharp PA. siRNA-directed inhibition of HIV-1 infection. Nat Med 2002; 8:681-6. PubMed
Hide