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Graham, Daniel

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Graham, Daniel

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Author's Publications: search.filters.isAuthorOfPublication.76dff839-0de0-44ce-b478-a7c8aae9071f

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    Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst
    (Nature Pub. Group, 2015) Graham, Daniel; Becker, Christine E.; Doan, Aivi; Goel, Gautam; Villablanca, Eduardo J.; Knights, Dan; Mok, Amanda; Ng, Aylwin C.Y.; Doench, John G.; Root, David E.; Clish, Clary B.; Xavier, Ramnik
    The phagocyte oxidative burst, mediated by Nox2 NADPH oxidase-derived reactive oxygen species, confers host defense against a broad spectrum of bacterial and fungal pathogens. Loss-of-function mutations that impair function of the Nox2 complex result in a life-threatening immunodeficiency, and genetic variants of Nox2 subunits have been implicated in pathogenesis of inflammatory bowel disease (IBD). Thus, alterations in the oxidative burst can profoundly impact host defense, yet little is known about regulatory mechanisms that fine-tune this response. Here we report the discovery of regulatory nodes controlling oxidative burst by functional screening of genes within loci linked to human inflammatory disease. Implementing a multi-omics approach, we define transcriptional, metabolic and ubiquitin-cycling nodes controlled by Rbpj, Pfkl and Rnf145, respectively. Furthermore, we implicate Rnf145 in proteostasis of the Nox2 complex by endoplasmic reticulum-associated degradation. Consequently, ablation of Rnf145 in murine macrophages enhances bacterial clearance, and rescues the oxidative burst defects associated with Ncf4 haploinsufficiency.
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    Resources for the design of CRISPR gene editing experiments
    (BioMed Central, 2015) Graham, Daniel; Root, David E.
    CRISPR-based approaches have quickly become a favored method to perturb genes to uncover their functions. Here, we review the key considerations in the design of genome editing experiments, and survey the tools and resources currently available to assist users of this technology.