Histone acetylation at the sulfotransferase 1a1 gene is associated with its hepatic expression in normal aging

Abstract

Objectives Phase II drug metabolism is poorly studied in advanced age and older adults may exhibit significant variability in their expression of phase II enzymes. We hypothesized that age-related changes to epigenetic regulation of genes involved in phase II drug metabolism may contribute to these effects. MethodsWe examined published epigenome-wide studies of human blood and identified the SULT1A1 and UGT1A6 genes as the top loci showing epigenetic changes with age. To assess possible functional alterations with age in the liver, we assayed DNA methylation (5mC) and histone acetylation changes around the mouse homologs Sult1a1 and Ugt1a6 in liver tissue from mice aged 4-32 months. ResultsOur sample shows a significant loss of 5mC at Sult1a1 (β = −1.08, 95% CI [−1.8, −0.2], SE = 0.38, P = 0.011), mirroring the loss of 5mC with age observed in human blood DNA at the same locus. We also detected increased histone 3 lysine 9 acetylation (H3K9ac) with age at Sult1a1 (β = 0.11, 95% CI [0.002, 0.22], SE = 0.05, P = 0.04), but no change to histone 3 lysine 27 acetylation (H3K27ac). Sult1a1 gene expression is significantly positively associated with H3K9ac levels, accounting for 23% of the variation in expression. We did not detect any significant effects at Ugt1a6. Conclusions Sult1a1 expression is under epigenetic influence in normal aging and this influence is more pronounced for H3K9ac than DNA methylation or H3K27ac in this study. More generally, our findings support the relevance of epigenetics in regulating key drug-metabolizing pathways. In the future, epigenetic biomarkers could prove useful to inform dosing in older adults.

Age-Dependent Energy Metabolism and Transcriptome Changes in Urine-Derived Stem Cells

“…In addition, UGT1A6 and UGT1A9 genes encode for two UGTs that are altered in the elderly. UGT1A6 expression shows altered epigenetic regulation with aging in human blood samples (Kronfol et al, 2021), while UGT1A9 expression has been shown to be decreased in the aged mouse liver (Warren et al, 2018). By performing a functional enrichment analysis, we found alterations in drug and estrogen metabolism and the modulation of the immune response in UDSCs from elderly female adults.…”

Aha1 Is an Autonomous Chaperone for SULT1A1

“…SULT1A1, an important phase-II xenobiotic metabolizing enzyme, is highly expressed in the liver and mediates the sulfonation of steroids, drugs, and carcinogens . SULT1A1 assumes a major role in the chemical and functional homeostasis of substrate chemicals and hormones. − Owing to its functions in the metabolism of xenobiotics and endogenous hormones, SULT1A1 and its regulation are implicated in the pathophysiology of liver disease , and cancer. , Hence, we decided to choose this protein for further investigation.…”

“…As a phase-II metabolic enzyme, SULT1A1 assumes a major role in chemical and functional homeostasis by adding sulfate groups to hydroxyl functionalities in substrate chemicals and hormones, thereby improving their solubilities and promoting their excretion. 27−29 Due to its function in the metabolism of xenobiotics, SULT1A1 and its aberrant regulation are implicated in the pathophysiology of liver disease 30,31 and cancer. 32,33 Therefore, the regulatory role of Aha1 in the expression level of SULT1A1 protein that we uncovered herein may provide an important basis for developing approaches toward therapeutic interventions of these diseases.…”

“…27 SULT1A1 assumes a major role in the chemical and functional homeostasis of substrate chemicals and hormones. 27−29 Owing to its functions in the metabolism of xenobiotics and endogenous hormones, SULT1A1 and its regulation are implicated in the pathophysiology of liver disease 30,31 and cancer. 32,33 Hence, we decided to choose this protein for further investigation.…”

Genome-wide analysis of hepatic DNA methylation reveals impact of epigenetic aging on xenobiotic metabolism and transport genes in an aged mouse model

“…Epigenetic processes profoundly affect the expression of genes involved in xenobiotic metabolism and transport [9,10] and upregulation of genes involved in xenobiotic detoxification is a common mechanism of increased longevity across phyla [11,12]. Recent studies in laboratory mice suggest that epigenetic aging may substantially alter the hepatic expression and function of some ADME genes [13,14]. However, comprehensive genome-wide studies of epigenetic aging effects on ADME genes have been limited.…”