H3K23/H3K36 hypoacetylation and HDAC1 up-regulation are associated with adverse consequences in obstructive sleep apnea patients

• Published in: Scientific reports Vol. 11; no. 1; p. 20697
• Main Authors: Chen, Yung-Che, Hsu, Po-Yuan, Chin, Chien-Hung, Hsiao, Chang-Chun, Liou, Chia-Wei, Wang, Ting-Ya, Lin, Yong-Yong, Lee, Chiu-Ping, Lin, Hsin-Ching, Lin, Meng-Chih, Su, Mao-Chang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.10.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 692/308; 692/4017; 692/53; 692/699; Acetylation; Adult; Apnea; C-reactive protein; C-Reactive Protein - genetics; Cardiovascular diseases; Case-Control Studies; Cohort Studies; Continuous positive airway pressure; Continuous Positive Airway Pressure - methods; Disorders of Excessive Somnolence - genetics; DNA methylation; DNA Methylation - genetics; Female; Health risks; Histone Deacetylase 1 - genetics; Histones; Histones - genetics; Humanities and Social Sciences; Humans; Hypertension; Hypoxia; Hypoxia - genetics; Hypoxia-inducible factor 1a; Jumonji Domain-Containing Histone Demethylases - genetics; Leukocytes (mononuclear); Leukocytes, Mononuclear - physiology; Male; Middle Aged; multidisciplinary; NADPH Oxidase 1 - genetics; Overexpression; Oxidative stress; Oxygenation; Patients; Peripheral blood mononuclear cells; Polysomnography - methods; Promoter Regions, Genetic - genetics; Science; Science (multidisciplinary); Sleep; Sleep and wakefulness; Sleep apnea; Sleep Apnea Syndromes - genetics; Sleep Apnea, Obstructive - genetics; Sleep disorders; Snoring - genetics; THP-1 Cells; Up-regulation; Up-Regulation - genetics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-00052-9

The aim of this study is to determine the roles of global histone acetylation (Ac)/methylation (me), their modifying enzymes, and gene-specific histone enrichment in obstructive sleep apnea (OSA). Global histone modifications, and their modifying enzyme expressions were assessed in peripheral blood mononuclear cells from 56 patients with OSA and 16 matched subjects with primary snoring (PS). HIF-1α gene promoter-specific H3K36Ac enrichment was assessed in another cohort (28 OSA, 8 PS). Both global histone H3K23Ac and H3K36Ac expressions were decreased in OSA patients versus PS subjects. H3K23Ac expressions were further decreased in OSA patients with prevalent hypertension. HDAC1 expressions were higher in OSA patients, especially in those with excessive daytime sleepiness, and reduced after more than 6 months of continuous positive airway pressure treatment. H3K79me3 expression was increased in those with high C-reactive protein levels. Decreased KDM6B protein expressions were noted in those with a high hypoxic load, and associated with a higher risk for incident cardiovascular events or hypertension. HIF-1α gene promoter-specific H3K36Ac enrichment was decreased in OSA patients versus PS subjects. In vitro intermittent hypoxia with re-oxygenation stimuli resulted in HDAC1 over-expression and HIF-1α gene promoter-specific H3K36Ac under-expression, while HDAC1 inhibitor, SAHA, reversed oxidative stress through inhibiting NOX1. In conclusions, H3K23/H3K36 hypoacetylation is associated with the development of hypertension and disease severity in sleep-disordered breathing patients, probably through up-regulation of HDAC1, while H3K79 hypermethylation is associated with higher risk of cardiovascular diseases, probably through down-regulation of KDM6B.