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      Epigenetics: A Potential Mechanism Involved in the Pathogenesis of Various Adverse Consequences of Obstructive Sleep Apnea

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          Abstract

          Epigenetics is defined as the heritable phenotypic changes which do not involve alterations in the DNA sequence, including histone modifications, non-coding RNAs, and DNA methylation. Recently, much attention has been paid to the role of hypoxia-mediated epigenetic regulation in cancer, pulmonary hypertension, adaptation to high altitude, and cardiorenal disease. In contrast to sustained hypoxia, chronic intermittent hypoxia with re-oxygenation (IHR) plays a major role in the pathogenesis of various adverse consequences of obstructive sleep apnea (OSA), resembling ischemia re-perfusion injury. Nevertheless, the role of epigenetics in the pathogenesis of OSA is currently underexplored. This review proposes that epigenetic processes are involved in the development of various adverse consequences of OSA by influencing adaptive potential and phenotypic variability under conditions of chronic IHR. Improved understanding of the interaction between genetic and environmental factors through epigenetic regulations holds great value to give deeper insight into the mechanisms underlying IHR-related low-grade inflammation, oxidative stress, and sympathetic hyperactivity, and clarify their implications for biomedical research.

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          Most cited references88

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          Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters

          While the methylation of DNA in 5′ promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear 1–5 . In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5′ CpG island (CGI) promoters, while a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences 5–10 . Tissue-specific intragenic methylation might reduce, 3 or, paradoxically, enhance transcription elongation efficiency 1,2,4,5 . Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes 11–15 . To investigate the role of intragenic methylation, we generated a map of DNA methylation from human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were revealed to be in intragenic and intergenic regions, while less than 3% of CpG islands in 5′ promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters 16 . The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus 17,18 and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.
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            Are animal models predictive for humans?

            It is one of the central aims of the philosophy of science to elucidate the meanings of scientific terms and also to think critically about their application. The focus of this essay is the scientific term predict and whether there is credible evidence that animal models, especially in toxicology and pathophysiology, can be used to predict human outcomes. Whether animals can be used to predict human response to drugs and other chemicals is apparently a contentious issue. However, when one empirically analyzes animal models using scientific tools they fall far short of being able to predict human responses. This is not surprising considering what we have learned from fields such evolutionary and developmental biology, gene regulation and expression, epigenetics, complexity theory, and comparative genomics.
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              Obstructive sleep apnea: current perspectives

              The prevalence of obstructive sleep apnea (OSA) continues to rise. So too do the health, safety, and economic consequences. On an individual level, the causes and consequences of OSA can vary substantially between patients. In recent years, four key contributors to OSA pathogenesis or “phenotypes” have been characterized. These include a narrow, crowded, or collapsible upper airway “anatomical compromise” and “non-anatomical” contributors such as ineffective pharyngeal dilator muscle function during sleep, a low threshold for arousal to airway narrowing during sleep, and unstable control of breathing (high loop gain). Each of these phenotypes is a target for therapy. This review summarizes the latest knowledge on the different contributors to OSA with a focus on measurement techniques including emerging clinical tools designed to facilitate translation of new cause-driven targeted approaches to treat OSA. The potential for some of the specific pathophysiological causes of OSA to drive some of the key symptoms and consequences of OSA is also highlighted.

                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                15 June 2019
                June 2019
                : 20
                : 12
                : 2937
                Affiliations
                [1 ]Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; yungchechen@ 123456yahoo.com.tw (Y.-C.C.); hsupowan@ 123456yahoo.com.tw (P.-Y.H.)
                [2 ]Department of Medicine, College of Medicine, Chang Gung University, Taouyan 33302, Taiwan
                [3 ]Department of medical research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
                [4 ]Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taouyan 33302, Taiwan
                Author notes
                [* ]Correspondence: cchsiao@ 123456mail.cgu.edu.tw (C.-C.H.); linmengchih@ 123456hotmail.com (M.-C.L.); Tel.: +886-7-731-7123 (ext. 8979) (C.-C.H.); +886-7-731-7123 (ext. 8199) (M.-C.L.)
                Author information
                https://orcid.org/0000-0001-8695-5227
                https://orcid.org/0000-0002-7275-4675
                Article
                ijms-20-02937
                10.3390/ijms20122937
                6627863
                31208080
                05cadddb-3899-4e6d-a1d8-9b2f0fe7dfbb
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 April 2019
                : 13 June 2019
                Categories
                Review

                Molecular biology
                obstructive sleep apnea,intermittent hypoxia with re-oxygenation,epigenetics,dna methylation,histone modification,non-coding rna

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