H3K9 Acetylation Level of 11β-HSD2 in Human Wharton’s Jelly-Derived Mesenchymal Stem Cells: A Potential Biomarker for Evaluating Susceptibility to Multiple Chronic Diseases in Adulthood

Abstract

Objective: A large number of studies have suggested that low birth weight fetuses were susceptible to fetal-originated diseases in adulthood. The purpose of this study was to investigate whether the histone 3 Lysine 9 (H3K9) acetylation level of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in human Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) was an early warning marker for the susceptibility of multiple chronic diseases in adulthood. Methods: The epigenetic and expressional abnormality of 11β-HSD2 in human WJ-MSCs induced by a variety of prenatal adverse xenobiotic factors were analyzed by real-time quantitative PCR (RT-qPCR), chromatin immunoprecipitation (ChIP) and western blotting (WB). The expression of insulin-like growth factor 1 (IGF1) in human WJ-MSCs after overexpression or knockdown of 11β-HSD2 gene was analyzed by RT-qPCR. Finally, immunofluorescence and ChIP-PCR were used to analyze the H3K9 acetylation level and expression of 11β-HSD2 in the human umbilical cord with intrauterine growth retardation (IUGR). Results: The mRNA and protein expression of 11β-HSD2 in WJ-MSCs were decreased after treatment with caffeine, nicotine, and ethanol. The histone acetylation level in 11β-HSD2 promoter region (H3K9) was significantly reduced simultaneously. In the proliferation model of WJ-MSCs, 300 nM of cortisol promoted the gene expression of the IGF1 pathway, while 1200 nM inhibited the gene expression of the IGF1 pathway. The expression of IGF1 treated with cortisol at 300 nM was decreased after overexpression of 11β-HSD2, while the expression of IGF1 was increased after treatment with 1200 nM cortisol. After knockdown of 11β-HSD2, the expression of IGF1 was decreased after treatment with 300 nM cortisol, and IGF1 gene expression decreased further after treatment with 1200 nM cortisol. Besides, the expression and H3K9 acetylation level of 11β-HSD2 in the IUGR-derived human umbilical cord was also reduced. Conclusion: The decreased expression and H3K9 acetylation level of 11β-HSD2 in WJ-MSCs induced by multiple xenobiotics exposures may mediate the decreased expression of IGF1. The H3K9 acetylation level of 11β-HSD2 in the human umbilical cord might be an early warning biomarker for evaluating susceptibility to multiple chronic diseases in adulthood.