TY - JOUR
T1 - Genetic and environmental factors regulate the type 1 diabetes gene CTSH via differential DNA methylation
AU - Ye, Jody
AU - Stefan-Lifshitz, Mihaela
AU - Tomer, Yaron
N1 - Funding Information:
Funding and additional information—This work was supported in part by grant National Institute of Diabetes and Digestive and Kidney Diseases R01, the National Institutes of Health (DK067555 to Y. T.), the Diabetes Research and Wellness Foundation UK nonclinical fellowship (N-C/2016/Ye to J. Y.), and the US Russell Berrie Foundation New York City Diabetes Fellowship (to J. Y.). J. Y. is the guarantor of this work, as such, had full access to all the data in the study, and takes responsibility for the integrity of the data and accuracy of the data analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2021 THE AUTHORS.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jbc.2021.100774
DO - 10.1016/j.jbc.2021.100774
M3 - Article
C2 - 33992646
AN - SCOPUS:85107235205
VL - 296
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
M1 - 00567
ER -