Genetic and environmental factors regulate the type 1 diabetes gene CTSH via differential DNA methylation
| Autor: | Yaron Tomer, Jody Ye, Mihaela Stefan-Lifshitz |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cathepsin H type 1 diabetes LD linkage disequilibrium HEK293 human embryonic kidney 293 cells Tet 10–11 translocation GADD45α growth arrest and DNA damage–45 alpha Biology IFN-γ interferon γ ACTB beta-actin Biochemistry DNA methyltransferase CpG cytosine–phosphate–guanine dinucleotide Epigenesis Genetic Proinflammatory cytokine IL-1β interleukin 1β 03 medical and health sciences GWAS Genome-Wide Association Studies genetic polymorphism Humans MS-qPCR methylation-specific quantitative PCR Epigenetics P/S penicillin–streptomycin Molecular Biology TNF-α tumor necrosis factor α DNA methylation epigenetics DMOG dimethyloxalylglycine 030102 biochemistry & molecular biology GTEx Genotype-Tissue Expression TDG thymine DNA glycosylase Cell Biology Methylation Molecular biology beta cell Chromatin Diabetes Mellitus Type 1 030104 developmental biology DNMT DNA methyltransferase CpG site TSS transcription start site CpG Islands Gene-Environment Interaction CTSH cathepsin H T1D type 1 diabetes EF-1α elongation factor 1α Research Article |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.100774 |
| Popis: | Cathepsin H (CTSH) is a type 1 diabetes (T1D) risk gene; large-scale genetic and epidemiological studies found that T1D genetic risk correlates with high CTSH expression, rapid decline of beta-cell function, and early onset T1D. Counterintuitively, transcriptional downregulation of CTSH by proinflammatory cytokines has been shown to promote beta-cell apoptosis. Here, we potentially explain these observed contrasting effects, describing a new mechanism where proinflammatory cytokines and T1D genetic risk variants regulate CTSH transcription via differential DNA methylation. We show that, in human islets, CTSH downregulation by the proinflammatory cytokine cocktail interleukin 1β + tumor necrosis factor α + interferon γ was coupled with DNA hypermethylation in an open chromatin region in CTSH intron 1. A luciferase assay in human embryonic kidney 293 cells revealed that methylation of three key cytosine-phosphate-guanine dinucleotide (CpG) residues in intron 1 was responsible for the reduction of promoter activity. We further found that cytokine-induced intron 1 hypermethylation is caused by lowered Tet1/3 activities, suggesting that attenuated active demethylation lowered CTSH transcription. Importantly, individuals who carry the T1D risk variant showed lower methylation variability at the intron 1 CpG residues, presumably making them less sensitive to cytokines, whereas individuals who carry the protective variant showed higher methylation variability, presumably making them more sensitive to cytokines and implying differential responses to environment between the two patient populations. These findings suggest that genetic and environmental influences on a T1D locus are mediated by differential variability and mean of DNA methylation. |
| Databáze: | OpenAIRE |
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