BBS Faculty Member - Carl Novina

Carl Novina

Department of Medicine

Dana Farber Cancer Institute
Smith Building, Room 552
450 Brookline Avenue
Boston, MA 02215
Tel: 617-582-7961
Fax: 617-582-7962
Email: carl_novina@dfci.harvard.edu
Visit my lab page here.



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 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.
Projects are available to understand 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. Traditional methods to define lncRNA-protein interactions focus on immunoprecipitating one candidate RNA with an RNA tag or antisense DNA oligos, or incubating cell lysates with biotinylated in vitro transcribed RNAs followed by mass spectrometry or western blotting. Not only are these methods low throughput, but the protein identification step is extremely challenging due to limited biomass from low-efficiency immunoprecipitations, loss of transient and weak interactors, or isolation of promiscuous RNA binding proteins. We are beginning to define lncRNA-dependent interactomes through development of a lncRNA-based yeast three hybrid (Y3H) platform.
Projects are available to systematically define lncRNA-protein interactomes for a set of cancer-promoting lncRNAs through implementation of RATA and Y3H systems.

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.

Projects are available to (1) reprogram methylation states at disease-relevant loci for therapy, especially for cancer immunotherapy; (2) compare methylation-dependent changes in microRNA transcription to oncogenic phenotypes; and (3) relate differential promoter methylation to changes in chromatin architecture and transcription factor binding at promoters.



Last Update: 11/15/2017



Publications

For a complete listing of publications click here.

 


 

Targeted DNA methylation in human cells using engineered dCas9-methyltransferases. Xiong T, Meister GE, Workman RE, Kato NC, Spellberg MC, Turker F, Timp W, Ostermeir M, Novina CD. Scientific Rep. 2017; 7(1):6732.

Prmt1-mediated translation regulation is a crucial vulnerability of cancer. Hsu JH-R, Hubbell-Engler B, Adelmant G, Huang J, Joyce C, Vazquez F, Weir B, Montgomery P, Tsherniak A, Giacomelli A, Perry J, Trowbridge J, Fujiwara Y, Cowley G, Xie H, Kim W, Novina CD, Hahn W, Marto J, Orkin S. Cancer Res. 2017. [Epub ahead of print].

The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection. 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. Nat. Immunol. 2017; 18(7):791-799.

RATA: A method for high-throughput identification of RNA bound transcription factors. Schmidt K, Buquicchio F, Carroll J, Distel RJ, Yoon CH, Novina CD.
J. Biol. Methods. 2017; 4(1), e67.

Differential regulation of the melanoma proteome by eIF4A1 and eIF4E. Joyce CE, Yanez, AG, Mori A, Yoda A, Carroll JS, Novina CD. Cancer Res. 2017 Feb 1;77(3):613-622.

The lncRNA SLNCR1 mediates melanoma invasion through a conserved SRA1-like region. Schmidt K, Joyce CE, Buquicchio F, Brown A, Ritz J, Distel RJ, Yoon CH, Novina CD. Cell Reports. 2016; 15(9):2025-37.



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