Cell Type- and Stimulation-Dependent Transcriptional Programs Regulated by Atg16L1 and Its Crohn's Disease Risk Variant T300A.

The Journal of Immunology : Official Journal of the American Association of Immunologists
Mukund VarmaRamnik Xavier

Abstract

Genome-wide association studies have identified common genetic variants impacting human diseases; however, there are indications that the functional consequences of genetic polymorphisms can be distinct depending on cell type-specific contexts, which produce divergent phenotypic outcomes. Thus, the functional impact of genetic variation and the underlying mechanisms of disease risk are modified by cell type-specific effects of genotype on pathological phenotypes. In this study, we extend these concepts to interrogate the interdependence of cell type- and stimulation-specific programs influenced by the core autophagy gene Atg16L1 and its T300A coding polymorphism identified by genome-wide association studies as linked with increased risk of Crohn's disease. We applied a stimulation-based perturbational profiling approach to define Atg16L1 T300A phenotypes in dendritic cells and T lymphocytes. Accordingly, we identified stimulus-specific transcriptional signatures revealing T300A-dependent functional phenotypes that mechanistically link inflammatory cytokines, IFN response genes, steroid biosynthesis, and lipid metabolism in dendritic cells and iron homeostasis and lysosomal biogenesis in T lymphocytes. Collectively, these studie...Continue Reading

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Citations

Sep 2, 2020·Current Opinion in Gastroenterology·Alberto Caminero, M I Pinto-Sanchez
Mar 23, 2021·The FEBS Journal·Daniel Hamaoui, Agathe Subtil

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