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, Medicine, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

The Novina lab combines basic science and advanced technologies to accelerate the translation of biological discoveries into novel therapies. Areas of focus in the lab include the role of non-coding RNAs in oncogenesis and epigenetic engineering of disease relevant loci – especially genes relevant for cancer immunotherapy – using our programmable DNA methyltransferase.

Long non-coding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes, especially cancers. Although dysregulated lncRNA expression has been associated with cancer progression, the contribution of lncRNAs to oncogenesis is poorly understood because their molecular and biological functions are obscure. We recently identified a novel lncRNA and its interacting proteins important for melanoma invasion. We are currently studying how this lncRNA functions at the molecular level, which may be important for determining why more males than females die from melanomas.

More broadly, the Novina lab is attempting to understand lncRNA biology and its roles in oncogenesis by systematically identifying lncRNA-associated proteins. It is virtually impossible to bioinformatically predict lncRNA function (or interacting proteins) by sequence analysis because (1) lncRNAs are poorly conserved and (2) proteins bind to RNAs by a poorly understood combination of RNA sequence and secondary structure. We are beginning to systematically define lncRNA-dependent interactomes through development of a lncRNA-based yeast three hybrid (Y3H) platform.

Regulatory RNAs are just one of many regulatory mechanisms that coordinate gene expression in normal and disease contexts. MicroRNA and lncRNA genes themselves are developmentally regulated and demonstrate altered epigenetic marks such as aberrant promoter hypo- and hyper-methylation, especially in cancers. Altered microRNA expression has been correlated with the tissue of origin, prognosis, and drug sensitivity of cancers and other diseases.

We recently described a novel tool for targeted DNA methylation by tethering a “split-fusion” methyltransferase to an endonuclease-deficient mutant Cas9. Our split-fusion approach minimizes off-target effects by ensuring that enzyme activity is specifically reconstituted at the targeted locus. We are also developing gRNA screening strategies to fine-tune targeting within each locus. How are epigenetic marks set, maintained, spread and inherited? How do establishing DNA marks relate to establishing histone marks? These fundamentally important questions must be answered to realize the full potential of epigenetic engineering in the clinic.

To develop this tool as a future epigenetic therapy, we are attempting to target DNA methylation to genes important for cancer immunotherapy. Specifically, we would like to repress checkpoint inhibitor genes which would increase T cell-mediated tumor killing. Additionally, we would like to repress “M2” polarizing genes in tumor-associated macrophages. Increasing “M1” polarization is expected to increase anti-tumor immune responses.

Publications

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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; 18:791-799. PubMed
  • 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. PubMed
  • Joyce CE, Yanez AG, Mori A, Yoda A, Carroll JS, Novina CD. Differential Regulation of the Melanoma Proteome by eIF4A1 and eIF4E. Cancer Res 2016; 77:613-622. PubMed
  • 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. PubMed
  • 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; 15:2025-37. PubMed
  • 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; 22:288-97. PubMed
  • 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; 344:1522-5. PubMed
  • 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
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