当前位置: X-MOL 学术J. Immunol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Cell Type– and Stimulation-Dependent Transcriptional Programs Regulated by Atg16L1 and Its Crohn's Disease Risk Variant T300A
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-10 , DOI: 10.4049/jimmunol.1900750
Mukund Varma 1 , Motohiko Kadoki 1, 2, 3 , Ariel Lefkovith 1 , Kara L Conway 2 , Kevin Gao 2 , Vishnu Mohanan 1, 2, 3 , Betsabeh Khoramian Tusi 1, 2, 3 , Daniel B Graham 1, 3, 4 , Isabel J Latorre 1, 2, 3 , Andrew C Tolonen 1 , Bernard Khor 2 , Aylwin Ng 4, 5 , Ramnik J Xavier 2, 3, 4, 5
Affiliation  

Key Points Stimulation-based profiling defined genotype- and cell-specific Atg16L1 programs. Cell type and stimulation strongly influence Atg16L1 T300A genotypic differences. Genotype- and stimulation-dependent lipid metabolism genes impair mucosal immunity. 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 studies highlight the combined effects of Atg16L1 genetic variation and stimulatory context on immune function.

中文翻译:

受 Atg16L1 及其克罗恩病风险变体 T300A 调控的细胞类型和刺激依赖性转录程序

关键点基于刺激的分析定义的基因型和细胞特异性 Atg16L1 程序。细胞类型和刺激强烈影响 Atg16L1 T300A 基因型差异。基因型和刺激依赖性脂质代谢基因损害粘膜免疫。全基因组关联研究已经确定了影响人类疾病的常见遗传变异;然而,有迹象表明,遗传多态性的功能后果可能因细胞类型特定的环境而异,这会产生不同的表型结果。因此,基因型对病理表型的细胞类型特异性影响改变了遗传变异的功能影响和疾病风险的潜在机制。在这项研究中,我们将这些概念扩展到询问受核心自噬基因 Atg16L1 及其 T300A 编码多态性影响的细胞类型和刺激特异性程序的相互依赖性,这些多态性通过全基因组关联研究确定与克罗恩病风险增加有关。我们应用基于刺激的微扰分析方法来定义树突状细胞和 T 淋巴细胞中的 Atg16L1 T300A 表型。因此,我们确定了刺激特异性转录特征,揭示了 T300A 依赖性功能表型,这些表型在机械上将树突状细胞中的炎性细胞因子、IFN 反应基因、类固醇生物合成和脂质代谢以及 T 淋巴细胞中的铁稳态和溶酶体生物发生联系起来。集体,
更新日期:2020-06-10
down
wechat
bug