BBS Faculty Member - Nir Hacohen

Nir Hacohen

Department of Medicine

Massachusetts General Hospital
149 13th Street, Room 8410
Charlestown, MA 02129
Tel: 617-724-3768
Fax: 617-726-5651
Email: nhacohen@partners.org
Visit my lab page here.



The Hacohen lab uses systems-wide genetic and biochemical approaches to describe the mechanisms underlying specificity in pathogen-sensing pathways, the interactions of pathogens with their hosts and the initiation of autoimmunity and tumor immunity. The major biological questions in the lab include how: (1) TLRs and other pathogen sensors achieve specificity in their induction of gene expression; (2) self DNA is sensed inappropriately in the context of autoimmunity; (3) tumor immunity is regulated. A common technological goal across these projects is to develop systematic methods to reconstruct signaling and transcriptional networks.

Initiating immunity in response to pathogens and self. The immune system can normally distinguish and respond appropriately to a broad diversity of pathogens and antigens that it encounters during a lifetime – including the products of bacteria, fungi, viruses and mammalian cells. Dendritic cells (DCs) play an important role in this process through their highly developed machinery to sense and engulf pathogens and to process and present digested peptides to T cells. We had previously shown that dendritic cells exhibit unique gene expression signatures, including specific cytokine, chemokine and costimulator expression, in response to distinct pathogens. Our current studies focus on revealing the genetic networks underlying innate immune responses and host-pathogen interactions. We are interested in addressing the following kinds of questions: (1) What are the mechanisms by which each innate sensor induces specific cellular responses? (2) What is the role of innate sensory pathways in the induction of protective immunity to infections and tumors? (3) How are these pathways dysregulated under some conditions, leading to inflammatory disorders or autoimmune disease? (4) How do pathogens manipulate the host response, and how does innate immune activation shift the balance to protect the host? To address these questions, we utilize genetic, biochemical and cell biological approaches to systematically dissect the genetic circuitry of pathogen-sensing pathways and their role in initiating and guiding immune responses.

RNAi library for loss-of-function genetics in mammalian cells. Genetic screening in lower organisms has been the basis of critical discoveries across many fields. To develop a method for systematic genetic screens in mammals, we have been part of a consortium that has: (a) generated genome-wide lentiviral shRNA libraries targeting human and mouse genes at the Broad Institute (Moffat et al., 2006; Luo et al., 2008); (b) developed high-throughput protocols to generate viral particles and infect cells in order to enable large-scale loss-of-function screens in mammalian cells; (c) demonstrated that these viruses can infect primary dendritic cells (and many other immune and non-immune cell types) and silence genes that control DC functions (Amit et al., 2009; Chevrier et al., 2011). As the Broad Institute RNAi Consortium and Platform continues to refine this technology and develop applications to many biological systems, we have begun to apply this powerful methodology to dissect the circuitry of the immune system (Oberdoerffer et al., 2008; Amit et al., 2009; Shapira et al., 2009; Chevrier et al., 2011). We are also working on adapting the libraries for in vivo RNAi screens and studies.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Amit I, Garber M, Chevrier N, Leite AP, Donner Y, Eisenhaure T, Guttman M, Grenier JK, Li W, Zuk O, Schubert LA, Birditt B, Shay T, Goren A, Zhang X, Smith Z, Deering R, McDonald RC, Cabili M, Bernstein BE, Rinn JL, Meissner A, Root DE, Hacohen N*^, Regev A*. Unbiased reconstruction of a mammalian transcriptional network mediating the differential response to pathogens. Science 2009 ; 326: 257-63. (* Equal contributors; ^corresponding author)

Shapira S, Gat-Viks I, Shum BOV, Dricot A, Degrace MM, Wu L, Gupta PB, Hao T, Silver SJ, Root DE, Hill DE, Regev A,
Hacohen N. A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell 2009; 139: 1255-67.

Astier A, Beriou G, Eisenhaure T, Anderton SM, Hafler D,
Hacohen N. RNAi screen in primary human T cells reveals Flt3 as a modulator of IL-10 levels. J. Immunology 2010; 184: 685-93.

Chevrier N, Mertins P, Artyomov MN, Shalek AK, Iannacone M, Ciaccio MF, Gat-Viks I, Tonti E, DeGrace MM, Clauser KR, Garber M, Eisenhaure TM, Yosef N, Robinson J, Sutton A, Andersen M, Root DE , von Andrian U, Jones RB, Park H, Carr SA, Regev A, Amit,I,
Hacohen N. Systematic Discovery of Signaling Components Identifies New Branches in Viral-Sensing Pathways. Cell 2011; 147: 853-867



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