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Carl Novina, MD, PhD


Researcher


Researcher

  • Associate Professor of Medicine, Dana-Farber Cancer Institute and Harvard Medical School
  • Associate Member, Broad Institute of Harvard and MIT

Contact Information

  • Office Phone Number(617) 582-7961
  • Fax(617) 582-7962

Bio

Dr. Novina received his M.D. from Columbia University, College of Physicians and Surgeons in 2000 and his Ph.D. from Tufts University, Sackler School of Graduate Biomedical Sciences in 1998. His graduate work resulted in 10 publications examining transcriptional regulation of TATA-less promoters in Ananda Roy’s laboratory. As a postdoctoral fellow in Phillip Sharp’s laboratory at the Massachusetts Institute of Technology, Dr. Novina studied the basic mechanisms of microRNAs, demonstrated the use of siRNAs to inhibit HIV infection (Nat Med. 8:681, 2002) and developed one of the first lentiviruses for the delivery of siRNAs to non-dividing mammalian cells (RNA 9:493, 2003), which became the host vector for The RNAi Consortium’s collection of lentivirus-expressed siRNAs.



In 2004, Dr. Novina joined the faculty at Dana-Farber Cancer Institute and Harvard Medical School. His laboratory has made several seminal insights into the fundamental biology of microRNAs and their dysregulation in cancers. His group reported the first fully cell-free microRNA-dependent translational repression reactions (Mol. Cell 22:553, 2006), used these reactions to reveal how microRNAs repress translation initiation by blocking 60S subunit joining to 40S ribosomes (PNAS 105:5343, 2008), discovered an RNA chaperone activity intrinsic to human Argonaute proteins (NSMB 16:1259, 2009) and an alternate mechanism of RISC assembly by Argonaute recruitment to microRNA-mRNA duplexes in vitro and in cells (RNA 18:2041, 2012), demonstrated the first example of an intronic microRNA (miR-211) that assumes the tumor suppressor role of its host gene (melastatin; Mol. Cell 40:841, 2010) and direct coupling between melastatin splicing and miR-211 microprocessing (PLoS Genet. (7)10:e10023302011, 2011). His group recently uncovered a potential tumor suppressor role for ribosomes in regulating microRNA function (Mol. Cell 46:171, 2012).

Location

Dana-Farber Cancer Institute
450 Brookline Avenue, Smith 570
Boston MA, 02215
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Research



Epigenetic engineering cancer immunotherapy



The Novina lab has focused on the molecular mechanisms of microRNAs and their dysregulation in cancers. Indeed, it is critical to understand how microRNA expression is controlled in normal and disease contexts. In mammals, many microRNAs are developmentally regulated and demonstrate altered epigenetic profiles, such as aberrant promoter hypo- and hyper-methylation, in cancers. Altered microRNA expression has been correlated with the tissue of origin, prognosis, and drug sensitivity of cancers and other diseases. To study the causes and consequences of inappropriate DNA methylation of microRNA and other disease-causing genes, the Novina lab is developing "epigenetic engineering" tools that will facilitate site-specific addition and removal of methyl groups on DNA.



To accomplish this, we have been employing the RNA-directed CRISPR-Cas9 system. There are two key components to this system that can be leveraged for epigenetic reprogramming: (1) the Cas9 protein is directed to specific DNA sequences by a complementary guide RNA (gRNA). Introducing multiple gRNAs can direct Cas9 to multiple sites within a promoter or to multiple different promoters simultaneously. (2) Cas9 is normally an endonuclease that cleaves foreign DNA; however, an endonuclease-deficient Cas9 (dCas9) mutant allows localization of dCas9 without cleavage. To methylate or demethylate DNA at precise sites in the genome, we have fused methyltransferases (MTases) or demethylases to dCas9. To avoid deleterious effects of off-target methylation/demethylation, we took a "split-fusion" approach in which the enzyme is split into two inactive halves that only regain functionality when co-recruited to a particular site. These dCas9-fusion proteins bound to selected gRNAs will allow us to specifically target discrete loci for repression (methylation) or induction (demethylation) of genes of interest.



Precise control over DNA methylation will enable specific reprogramming of cell fates for experimental and therapeutic purposes. My lab is using these tools to (1) relate differential promoter methylation to changes in chromatin architecture and transcription factor binding at promoters; (2) compare methylation-dependent changes in microRNA transcription to oncogenic phenotypes; and (3) develop epigenetic reprogramming strategies for a variety of human diseases. A major initiative in my lab is using dCas9-MTases to target genes that repress immune responses. Our goal is to silence repressive protein-coding and non-coding genes to improve the efficacy of T cell-based cancer immunotherapy. We believe that a robust platform for epigenetic engineering will enable novel therapies against cancer and other diseases.



Moffett HF, Cartwright ANR, Kim HJ, Godec J, Pyrdol J, Äijö T, Martinez GJ, Rao A, Lu J, Golub TR, Cantor H, Sharpe AH, Novina CD, Wucherpfennig KW. Erratum: The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection. Nat Immunol. 2017 Sep 19; 18(10):1173.
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Hsu JH, Hubbell-Engler B, Adelmant G, Huang J, Joyce CE, Vazquez F, Weir BA, Montgomery P, Tsherniak A, Giacomelli AO, Perry JA, Trowbridge J, Fujiwara Y, Cowley GS, Xie H, Kim W, Novina CD, Hahn WC, Marto JA, Orkin SH. PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer. Cancer Res. 2017 Sep 01; 77(17):4613-4625.
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Moffett HF, Cartwright ANR, Kim HJ, Godec J, Pyrdol J, Äijö T, Martinez GJ, Rao A, Lu J, Golub TR, Cantor H, Sharpe AH, Novina CD, Wucherpfennig KW. The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection. Nat Immunol. 2017 Jul; 18(7):791-799.
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Schmidt K, Buquicchio F, Carroll JS, Distel RJ, Novina CD. RATA: A method for high-throughput identification of RNA bound transcription factors. J Biol Methods. 2017; 4(1).
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Joyce CE, Yanez AG, Mori A, Yoda A, Carroll JS, Novina CD. Differential Regulation of the Melanoma Proteome by eIF4A1 and eIF4E. Cancer Res. 2017 Feb 01; 77(3):613-622.
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Izar B, Joyce CE, Goff S, Cho NL, Shah PM, Sharma G, Li J, Ibrahim N, Gold J, Hodi FS, Garraway LA, Novina CD, Bertagnolli MM, Yoon CH. Bidirectional cross talk between patient-derived melanoma and cancer-associated fibroblasts promotes invasion and proliferation. Pigment Cell Melanoma Res. 2016 Nov; 29(6):656-668.
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Schmidt K, Joyce CE, Buquicchio F, Brown A, Ritz J, Distel RJ, Yoon CH, Novina CD. The lncRNA SLNCR1 Mediates Melanoma Invasion through a Conserved SRA1-like Region. Cell Rep. 2016 05 31; 15(9):2025-37.
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Schneider RK, Schenone M, Ferreira MV, Kramann R, Joyce CE, Hartigan C, Beier F, Brümmendorf TH, Germing U, Platzbecker U, Büsche G, Knüchel R, Chen MC, Waters CS, Chen E, Chu LP, Novina CD, Lindsley RC, Carr SA, Ebert BL. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med. 2016 Mar; 22(3):288-97.
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Traeger LL, Volkening JD, Moffett H, Gallant JR, Chen PH, Novina CD, Phillips GN, Anand R, Wells GB, Pinch M, Güth R, Unguez GA, Albert JS, Zakon H, Sussman MR, Samanta MP. Unique patterns of transcript and miRNA expression in the South American strong voltage electric eel (Electrophorus electricus). BMC Genomics. 2015 Mar 26; 16:243.
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Gallant JR, Traeger LL, Volkening JD, Moffett H, Chen PH, Novina CD, Phillips GN, Anand R, Wells GB, Pinch M, Güth R, Unguez GA, Albert JS, Zakon HH, Samanta MP, Sussman MR. Nonhuman genetics. Genomic basis for the convergent evolution of electric organs. Science. 2014 Jun 27; 344(6191):1522-5.
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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 Jul 29; 210(8):1545-57.
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Joyce CE, Novina CD. miR-155 in acute myeloid leukemia: not merely a prognostic marker? J Clin Oncol. 2013 Jun 10; 31(17):2219-21.
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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 May 09; 50(3):356-67.
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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 Nov; 18(11):2041-55.
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Janas MM, Wang E, Love T, Harris AS, Stevenson K, Semmelmann K, Shaffer JM, Chen PH, Doench JG, Yerramilli SV, Neuberg DS, Iliopoulos D, Housman DE, Burge CB, Novina CD. Reduced expression of ribosomal proteins relieves microRNA-mediated repression. Mol Cell. 2012 Apr 27; 46(2):171-86.
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Janas MM, Novina CD. Not lost in translation: stepwise regulation of microRNA targets. EMBO J. 2012 May 30; 31(11):2446-7.
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Janas MM, Khaled M, Schubert S, Bernstein JG, Golan D, Veguilla RA, Fisher DE, Shomron N, Levy C, Novina CD. Feed-forward microprocessing and splicing activities at a microRNA-containing intron. PLoS Genet. 2011 Oct; 7(10):e1002330.
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Novina CD. New insights into the biology of melanomas using a microRNA tool-KIT. Cell Cycle. 2011 Sep 01; 10(17):2828-9.
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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 Apr 11; 208(4):663-75.
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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 Mar 08; 6(3):e16956.
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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 Dec 10; 40(5):841-9.
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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 Dec; 16(12):1259-66.
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Omer AD, Janas MM, Novina CD. The chicken or the egg: microRNA-mediated regulation of mRNA translation or mRNA stability. Mol Cell. 2009 Sep 24; 35(6):739-40.
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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. 2009 Mar; 83(5):2357-67.
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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 Waldenström macroglobulinemia. Blood. 2009 Apr 30; 113(18):4391-402.
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Wang B, Yanez A, Novina CD. MicroRNA-repressed mRNAs contain 40S but not 60S components. Proc Natl Acad Sci U S A. 2008 Apr 08; 105(14):5343-8.
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Love TM, Moffett HF, Novina CD. Not miR-ly small RNAs: big potential for microRNAs in therapy. J Allergy Clin Immunol. 2008 Feb; 121(2):309-19.
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Novina CD, Chabner BA. RNA-Directed Therapy: The Next Step in the miRNA Revolution. Oncologist. 2008 Jan; 13(1):1-3.
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Wang B, Doench JG, Novina CD. Analysis of microRNA effector functions in vitro. Methods. 2007 Oct; 43(2):91-104.
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Moffett HF, Novina CD. A small RNA makes a Bic difference. Genome Biol. 2007; 8(7):221.
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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 Jan; 117(1):112-21.
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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 Oct 20; 24(2):301-8.
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Wang B, Love TM, Call ME, Doench JG, Novina CD. Recapitulation of short RNA-directed translational gene silencing in vitro. Mol Cell. 2006 May 19; 22(4):553-60.
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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 Sep 23; 280(38):32736-45.
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Chowdhury D, Novina CD. Potential roles for short RNAs in lymphocytes. Immunol Cell Biol. 2005 Jun; 83(3):201-10.
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Chowdhury D, Novina CD. RNAi and RNA-based regulation of immune system function. Adv Immunol. 2005; 88:267-92.
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Novina CD, Sharp PA. The RNAi revolution. Nature. 2004 Jul 08; 430(6996):161-4.
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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 Jul; 77(13):7174-81.
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Dykxhoorn DM, Novina CD, Sharp PA. Killing the messenger: short RNAs that silence gene expression. Nat Rev Mol Cell Biol. 2003 Jun; 4(6):457-67.
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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 Apr; 9(4):493-501.
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Fan Z, Beresford PJ, Zhang D, Xu Z, Novina CD, Yoshida A, Pommier Y, Lieberman J. Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Nat Immunol. 2003 Feb; 4(2):145-53.
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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 Jul; 8(7):681-6.
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Morikawa N, Clarke TR, Novina CD, Watanabe K, Haqq C, Weiss M, Roy AL, Donahoe PK. Human Müllerian-inhibiting substance promoter contains a functional TFII-I-binding initiator. Biol Reprod. 2000 Oct; 63(4):1075-83.
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Novina CD, Kumar S, Bajpai U, Cheriyath V, Zhang K, Pillai S, Wortis HH, Roy AL. Regulation of nuclear localization and transcriptional activity of TFII-I by Bruton's tyrosine kinase. Mol Cell Biol. 1999 Jul; 19(7):5014-24.
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Novina CD, Cheriyath V, Roy AL. Regulation of TFII-I activity by phosphorylation. J Biol Chem. 1998 Dec 11; 273(50):33443-8.
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Cheriyath V, Novina CD, Roy AL. TFII-I regulates Vbeta promoter activity through an initiator element. Mol Cell Biol. 1998 Aug; 18(8):4444-54.
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Roy AL, Du H, Gregor PD, Novina CD, Martinez E, Roeder RG. Cloning of an inr- and E-box-binding protein, TFII-I, that interacts physically and functionally with USF1. EMBO J. 1997 Dec 01; 16(23):7091-104.
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Grueneberg DA, Henry RW, Brauer A, Novina CD, Cheriyath V, Roy AL, Gilman M. A multifunctional DNA-binding protein that promotes the formation of serum response factor/homeodomain complexes: identity to TFII-I. Genes Dev. 1997 Oct 01; 11(19):2482-93.
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Novina CD, Cheriyath V, Denis MC, Roy AL. Methods for studying the biochemical properties of an Inr element binding protein: TFII-I. Methods. 1997 Jul; 12(3):254-63.
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Novina CD, Roy AL. Core promoters and transcriptional control. Trends Genet. 1996 Sep; 12(9):351-5.
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Manzano-Winkler B, Novina CD, Roy AL. TFII is required for transcription of the naturally TATA-less but initiator-containing Vbeta promoter. J Biol Chem. 1996 May 17; 271(20):12076-81.
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