• Researcher Profile

    Carl Novina, MD, PhD

    Carl Novina, MD, PhD
    Associate Professor, Dana-Farber Cancer Institute & Harvard Medical School
    Associate Member, Broad Institute of Harvard and MIT

    Office phone: 617-582-7961
    Fax: 617-582-7962
    Email: carl_novina@dfci.harvard.edu

    Preferred contact method: email

    Research Department

    Cancer Immunology and Virology

    Area of Research

    Biology and dysregulation of microRNAs; epigenetic engineering of disease-relevent genes

    Dana-Farber Cancer Institute
    450 Brookline Avenue
    Dana 1420B
    Boston, MA 02215


    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).


    Biology and dysregulation of microRNAs; epigenetic engineering of disease-relevent genes

    The Novina Lab studies the fundamental biology of microRNAs, their dysregulation in cancers and their use as biomedical tools. In technology development, we are developing a pipeline for studying single cell transcriptomes from rare cells such as circulating tumor cells and hematopoietic progenitor cells from patients suffering bone marrow failure syndromes. A short summary of recent accomplishments and current research in our lab is described below.

    We performed mRNA and matched microRNA expression profiling of 55 human melanoma patient samples. We used this data to define a melanoma metastasis-specific network regulated by a melanocyte-specific microRNA (miR-211) expressed from intron 6 of a suspected melanoma tumor suppressor gene (melastatin). We found that reduced miR-211 but not reduced melastatin increases melanoma invasion and identified miR-211-regulated genes responsible for melanoma invasion and migration (Levy 2010). This is the first demonstration that a microRNA expressed internally from a protein-coding gene can assume the tumor suppressor function previously ascribed to its host gene. We are currently developing a single cell RNA-sequencing pipeline to examine individual cellular heterogeneity of melanoma circulating tumor cells as the source of melanoma metastasis and drug resistance.

    In another line of investigation, we developed a cell-based reporter to monitor microRNA-mediated repression of protein synthesis. Using this tool, we demonstrated that ribosomal protein coding genes (RPGs) as a class are important regulators of microRNA activity (Janas 2012). We showed that reduced expression of any RPG selectively increased protein synthesis of target mRNAs by a mechanism involving the tumor suppressor p53. Our observations may provide the molecular basis for altered gene expression in a group of rare genetic diseases called ribosomopathies (characterized by reduced ribosome biogenesis and function) including Diamond Blackfan Anemia (DBA), Shwachman Diamond Syndrome (SDS), and Dyskeratosis Congenita.

    These findings have important ramifications in explaining mechanisms by which ribosomopathies predispose to cancers. Clinically, these patients present with congenital anomalies, bone marrow failure (lineage-specific and pan-anemias) and cancer predisposition. Because microRNAs frequently target body patterning genes, differentiation and developmental genes as well as oncogenes, our observations potentially provide an explanation for this constellation of clinical findings. Additionally, interrogating the Cancer Cell Line Encyclopedia (CCLE), we identified breast cancers, small cell lung cancer, non-small cell lung cancer and glioblastomas with statistically-significant reductions in RPG expression. Currently, we are employing high-resolution polysome profiling and single cell analyses of patient bone marrow samples to further test our model.

    Altered microRNA expression has been correlated with the tissue of origin, prognosis, and drug sensitivity of cancers and other diseases. 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 and other disease-causing genes, my lab is developing “epigenetic engineering” tools that will enable site-specific addition and removal of methyl groups on DNA.

    To accomplish this, my lab has recently turned to another RNA-directed process, the Cas9-CRISPR system. There are two key components to this system which 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.

    Precise control over DNA methylation will enable specific reprogramming of cell fates for experimental and therapeutic purposes. A major new initiative in my lab is using Cas9-MTases that target genes which 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. I believe that a robust platform for epigenetic engineering will enable novel therapies against cancer, ribosomopathies and other diseases.

    By understanding biological processes at the most fundamental levels, we are gaining greater insights into disease processes and developing the tools to treat these diseases.


    • Brown, Adam, Graduate Student
    • Carroll, Johanna, PhD
    • Joyce, Cailin, PhD
    • Meister, Glenna, PhD
    • Schmidt, Karyn, PhD
    • Tremaglio, Chadene, PhD
    • Yanez, Adrienne, Graduate Student
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