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

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 T300Adependent 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.

AR12 (OSU-03012) suppresses GRP78 expression and inhibits SARS-CoV-2 replication

“…Many environmental and societal factors have been suggested to play causal roles in this epidemiology. One factor we have considered is the differential isoform expression of the autophagy regulatory protein ATG16L1 between African-Americans and European-Americans [17] , [18] , [19] , [20] , [21] , [22] . African-Americans have been found to express ATG16L1 T300 to a greater extent than European-Americans who more frequently express ATG16L1 A300; homozygous expression of ATG16L1 A300 is associated with a greater incidence of Crohn’s Disease, due to a reduced ability of immune cells to phagocytose and digest, via autophagy, inflammatory materials in the GI.…”

“…There are relatively few biomarkers that can be used to define altered biology between different populations of humans. One such biomarker is ATG16L1 [17] , [18] , [19] , [20] , [21] , [22] . In our oncology studies, expression of the isoform most commonly found in African Americans, ATG16L1 T300, predicted for enhanced tumor cell killing when treating the cells with agents that utilize autophagosome formation as a component of their killing mechanism [14] .…”

The Role of Autophagy in Inflammatory Bowel Disease

“…They demonstrated that compared with that from UC patients or healthy controls, the survival rate of adherent-invasive E. coli was significantly increased in CD patients with CD-associated polymorphism IRGM ( p = 0.05) and decreased in those with polymorphisms CD-associated XBP-1 ( p = 0.026) and CD-associated ULK-1 ( p = 0.033; Rioux et al, 2007 ). In addition, some single nucleotide polymorphisms (SNPs) of ATG16L1 , such as rs2241880 and rs6754677, have been detected in CD patients and shown to be associated with CD onset ( Baradaran Ghavami et al, 2019 ; Buisson et al, 2019 ; Kee et al, 2020 ; Tsianos et al, 2020 ; Varma et al, 2020 ). NOD2 is an important autophagy inducer via recruiting ATG16L1 into the cell membrane ( Park and Jeen, 2019 ).…”

Crohn's disease-associated ATG16L1 T300A genotype is associated with improved survival in gastric cancer

“…In CD, increased crypt base apoptosis leads to Paneth cell defect, resulting in diminished innate immunity and dysbiosis, whereas, in gastric cancer, increased tumor apoptosis without concomitant increase in tumor proliferation leads to improved survival. This is supported by a recent study demonstrating the T300A phenotype differences are stimulation (environmental factors)-and cell type-dependent [57]. On the other hand, survival benefit of the T300A/T300A genotype has also been shown in colorectal and non- small cell lung cancers [55,58].…”