TY - JOUR
T1 - Role of isocitrate dehydrogenase 2 on DNA hydroxymethylation in human airway smooth muscle cells
AU - Yeung, Bonnie H.Y.
AU - Huang, Jessie
AU - An, Steven S.
AU - Solway, Julian
AU - Mitzner, Wayne
AU - Tang, Wan Yee
N1 - Funding Information:
Supported by National Institute of Environmental Health Sciences grant ES-024784 (W.-y.T.) and U.S. National Heart, Lung, and Blood Institute grant HL-114471 (S.S.A.).
Publisher Copyright:
© 2020 by the American Thoracic Society.
PY - 2020/7
Y1 - 2020/7
N2 - Global DNA hydroxymethylation mediated by the TET (ten-eleven translocation) enzyme was induced in allergen-induced airway hyperresponsiveness in mouse lung tissues and specifically in isolated airway smooth muscle (ASM) cells. TET is an a-ketoglutarate (a-KG)-dependent enzyme, and the production of a-KG is catalyzed by IDH (isocitrate dehydrogenase). However, the role of IDH in the regulation of DNA hydroxymethylation in ASM cells is unknown. In comparison with nonasthmatic cells, asthmatic ASM cells exhibited higher TET activity and IDH2 (but not IDH-1 or IDH-3) gene expression levels. We modified the expression of IDH2 in ASM cells from humans with asthma by siRNA and examined the a-KG levels, TET activity, global DNA hydroxymethylation, cell proliferation, and expression of ASM phenotypic genes. Inhibition of IDH2 in asthmatic ASM cells decreased the a-KG levels, TET activity, and global DNA hydroxymethylation, and reversed the aberrant ASM phenotypes (including decreased cell proliferation and ASM phenotypic gene expression). Specifically, asthmatic cells transfected with siRNA against IDH2 showed decreased 5hmC (5-hydroxymethylcytosine) levels at the TGFB2 (transforming growth factor-b2) promoter determined by oxidative bisulfite sequencing. Taken together, our findings reveal that IDH2 plays an important role in the epigenetic regulation of ASM phenotypic changes in asthmatic ASM cells, suggesting that IDH2 is a potential therapeutic target for reversing the abnormal phenotypes seen in asthma.
AB - Global DNA hydroxymethylation mediated by the TET (ten-eleven translocation) enzyme was induced in allergen-induced airway hyperresponsiveness in mouse lung tissues and specifically in isolated airway smooth muscle (ASM) cells. TET is an a-ketoglutarate (a-KG)-dependent enzyme, and the production of a-KG is catalyzed by IDH (isocitrate dehydrogenase). However, the role of IDH in the regulation of DNA hydroxymethylation in ASM cells is unknown. In comparison with nonasthmatic cells, asthmatic ASM cells exhibited higher TET activity and IDH2 (but not IDH-1 or IDH-3) gene expression levels. We modified the expression of IDH2 in ASM cells from humans with asthma by siRNA and examined the a-KG levels, TET activity, global DNA hydroxymethylation, cell proliferation, and expression of ASM phenotypic genes. Inhibition of IDH2 in asthmatic ASM cells decreased the a-KG levels, TET activity, and global DNA hydroxymethylation, and reversed the aberrant ASM phenotypes (including decreased cell proliferation and ASM phenotypic gene expression). Specifically, asthmatic cells transfected with siRNA against IDH2 showed decreased 5hmC (5-hydroxymethylcytosine) levels at the TGFB2 (transforming growth factor-b2) promoter determined by oxidative bisulfite sequencing. Taken together, our findings reveal that IDH2 plays an important role in the epigenetic regulation of ASM phenotypic changes in asthmatic ASM cells, suggesting that IDH2 is a potential therapeutic target for reversing the abnormal phenotypes seen in asthma.
KW - A-ketoglutarate
KW - Airway smooth muscle cells
KW - DNA hydroxymethylation
KW - Isocitrate dehydrogenase 2
KW - Ten-eleven translocation
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U2 - 10.1165/rcmb.2019-0323OC
DO - 10.1165/rcmb.2019-0323OC
M3 - Article
C2 - 32150688
AN - SCOPUS:85087470151
SN - 1044-1549
VL - 63
SP - 36
EP - 45
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 1
ER -