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Yosef, Nir

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Yosef

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Nir

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Yosef, Nir

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2011 - 20135

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Author's Publications: search.filters.isAuthorOfPublication.668fe204-1220-4c74-8e05-7168629b418e

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Now showing 1 - 5 of 5
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    Dynamic regulatory network controlling Th17 cell differentiation
    (2013) Yosef, Nir; Shalek, Alex K.; Gaublomme, Jellert; Jin, Hulin; Lee, Youjin; Awasthi, Amit; Wu, Chuan; Karwacz, Katarzyna; Xiao, Sheng; Jorgolli, Marsela; Gennert, David; Satija, Rahul; Shakya, Arvind; Lu, Diana Y.; Trombetta, John J.; Pillai, Meenu R.; Ratcliffe, Peter J.; Coleman, Mathew L.; Bix, Mark; Tantin, Dean; Park, Hongkun; Kuchroo, Vijay; Regev, Aviv
    Despite their importance, the molecular circuits that control the differentiation of naĂŻve T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here, we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based tools for performing perturbations in primary T cells to systematically derive and experimentally validate a model of the dynamic regulatory network that controls Th17 differentiation. The network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, whose coupled action may be essential for maintaining the balance between Th17 and other CD4+ T cell subsets. Overall, our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles, and highlights novel drug targets for controlling Th17 differentiation.
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    Induction of pathogenic Th17 cells by inducible salt sensing kinase SGK1
    (2013) Wu, Chuan; Yosef, Nir; Thalhamer, Theresa; Zhu, Chen; Xiao, Sheng; Kishi, Yasuhiro; Regev, Aviv; Kuchroo, Vijay
    Th17 cells are highly proinflammatory cells critical for clearing extracellular pathogens and for induction of multiple autoimmune diseases1. IL-23 plays a critical role in stabilizing and reinforcing the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing Th17 cells with pathogenic effector functions2, 3. However, the precise molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions has not been elucidated. Here, we used transcriptional profiling of developing Th17 cells to construct a model of their signaling network and nominate major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1), a serine-threonine kinase4, as an essential node downstream of IL-23 signaling. SGK1 is critical for regulating IL-23R expression and stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na+ transport and salt (NaCl) homeostasis in other cells5, 6, 7, 8. We here show that a modest increase in salt concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated Na+-mediated Th17 differentiation in an IL-23-dependent manner. These data demonstrate that SGK1 plays a critical role in the induction of pathogenic Th17 cells and provides a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers Th17 development and promotes tissue inflammation.
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    Densely Interconnected Transcriptional Circuits Control Cell States in Human Hematopoiesis
    (Elsevier BV, 2011) Novershtern, Noa; Subramanian, Aravind; Lawton, Lee N.; Mak, Raymond; Haining, William; McConkey, Marie E.; Habib, Naomi; Yosef, Nir; Chang, Cindy; Shay, Tal; Frampton, Garrett M.; Drake, Adam C.B.; Leskov, Ilya; Nilsson, Bjorn; Preffer, Frederic; Dombkowski, David; Evans, John W.; Liefeld, Ted; Smutko, John S.; Chen, Jianzhu; Friedman, Nir; Young, Richard A.; Golub, Todd; Regev, Aviv; Ebert, Benjamin
    While many individual transcription factors are known to regulate hematopoietic differentiation, major aspects of the global architecture of hematopoiesis remain unknown. Here, we profiled gene expression in 38 distinct purified populations of human hematopoietic cells and used probabilistic models of gene expression and analysis of cis-elements in gene promoters to decipher the general organization of their regulatory circuitry. We identified modules of highly co-expressed genes, some of which are restricted to a single lineage, but most are expressed at variable levels across multiple lineages. We found densely interconnected cis-regulatory circuits and a large number of transcription factors that are differentially expressed across hematopoietic states. These findings suggest a more complex regulatory system for hematopoiesis than previously assumed.
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    Induction and molecular signature of pathogenic TH17 cells
    (2012) Lee, Youjin; Awasthi, Amit; Yosef, Nir; Quintana, Francisco; Xiao, Sheng; Peters, Anneli; Wu, Chuan; Kleinewietfeld, Markus; Kunder, Sharon; Hafler, David; Sobel, Raymond A.; Regev, Aviv; Kuchroo, Vijay
    Interleukin 17 (IL-17)-producing TH17 cells are often present at the sites of tissue inflammation in autoimmune diseases, which has lead to the conclusion that TH17 are main drivers of autoimmune tissue injury. However, not all TH17 cells are pathogenic, in fact TH17 generated with TGF-β1 and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23. Here we show that TGF-β3, produced by developing TH17 cells, is dependent on IL-23, which together with IL-6 induces highly pathogenic TH17 cells. Moreover, TGF-β3-induced TH17 cells are functionally and molecularly distinct from TGF-β1-induced TH17 cells and possess a molecular signature that defines pathogenic effector TH17 cells in autoimmune disease.
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    Nanowire-Mediated Delivery Enables Functional Interrogation of Primary Immune Cells: Application to the Analysis of Chronic Lymphocytic Leukemia
    (American ChemicalSociety, 2012) Shalek, Alexander; Gaublomme, Jellert; Wang, Lili; Yosef, Nir; Chevrier, Nicolas; Andersen, Mette S.; Robinson, Jacob T.; Pochet, Nathalie; Neuberg, Donna; Gertner, Rona; Amit, Ido; Brown, Jennifer; Hacohen, Nir; Regev, Aviv; Wu, Catherine; Park, Hongkun
    A circuit level understanding of immune cells and hematological cancers has been severely impeded by a lack of techniques that enable intracellular perturbation without significantly altering cell viability and function. Here, we demonstrate that vertical silicon nanowires (NWs) enable gene-specific manipulation of diverse murine and human immune cells with negligible toxicity. To illustrate the power of the technique, we then apply NW-mediated gene silencing to investigate the role of the Wnt signaling pathway in chronic lymphocytic leukemia (CLL). Remarkably, CLL-B cells from different patients exhibit tremendous heterogeneity in their response to the knockdown of a single gene, LEF1. This functional heterogeneity defines three distinct patient groups not discernible by conventional CLL cytogenetic markers and provides a prognostic indicator for patients’ time to first therapy. Analyses of gene expression signatures associated with these functional patient subgroups reveal unique insights into the underlying molecular basis for disease heterogeneity. Overall, our findings suggest a functional classification that can potentially guide the selection of patient-specific therapies in CLL and highlight the opportunities for nanotechnology to drive biological inquiry.