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Epigenetics of exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Daniel C. Turner, Robert A. Seaborne, Adam P. Sharples
Within the cell nucleus, approximately 150 bp of double helical DNA is tightly wrapped around four pairs of histone proteins (H2A, H2B, H3 and H4) which acts as a scaffold to enable the condensed packaging of DNA. These protein complexes are termed the nucleosomes and are often referred to as ‘beads on a string’ owing to their appearance (see Chapter 3, Figure 3.11). Each nucleosome complex is separated by short strands (~20–90 bp) of ‘linker’ DNA that is often subjected to epigenetic modifications, specifically DNA methylation. As described in Chapter 3, DNA is composed of four different nucleotides; the purine base nucleotides, adenine (A) and guanine (G), and the pyrimidine base nucleotides, thymine (T) and cytosine (C). Traditionally, it is the ‘C’ nucleotides within the DNA that are susceptible to methylation modification, which involves the biochemical attachment of a covalent methyl (CH3) chemical group to the 5th position of the pyrimidine ring of the ‘C’ nucleotide, resulting in 5-methylcytosine (5mC) (see Figure 6.1). Methylation of these cytosine nucleotides occurs in the context of CpG dinucleotide positions, also known as CpG sites. CpG sites are characterised by the presence of a cytosine nucleotide followed by a guanine nucleotide that are linked by a phosphate (‘p’) group within the same strand of DNA. This process therefore yields increased methylation, which is more commonly referred to as ‘hyper’-methylation when looking at whether exercise changes (or differentially methylates) the methylation status of a CpG site.
Epigenetics in Sperm, Epigenetic Diagnostics, and Transgenerational Inheritance
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Jennifer L. M. Thorson, Millissia Ben Maamar, Michael K. Skinner
DNA methylation was the first epimutation to be characterized. DNA methylation involves a small (methyl) chemical group that is enzymatically attached to DNA through DNA methyltransferase (DNMT), primarily at the cytosine base when adjacent to guanine in most species (20,21) and the product is 5-methylcytosine (5mC) (Figure 7.1). In mammals, the addition of a methyl group to a CpG site results in the alteration (often inhibition) of a transcription factor binding to DNA, while the removal of a methyl group to a CpG site facilitates the recruiting of proteins involved in gene expression (22). Other chemical modifications of cytosine bases in DNA have since been described, but are infrequent and function not elucidated. The ten-eleven translocation (TET) family of enzymes can successively oxidize 5mC to 5-hydroxymethylcytosine (5hmC), which is the precursor to DNA methylation erasure (23). In broad terms, the presence of 5mC often represses DNA transcription, while 5hmC is permissive to transcription (24,25). The functions of the other epigenetic modifications to cytosine are under investigation. N(6)-methyladenine is an epigenetic modification to the adenine base of DNA that was once thought to only be present in prokaryotic organisms, but has now been described in mammalian embryonic stem cells associated with RNA methylation (26).
Developmental plasticity, epigenetic mechanisms and early life influences on adult health and disease: Fundamental concepts
Published in Nicholas C. Harvey, Cyrus Cooper, Osteoporosis: a lifecourse epidemiology approach to skeletal health, 2018
Elizabeth M Curtis, Karen Lillycrop, Mark Hanson
The association between early life exposures and epigenetic changes in key metabolic regulatory genes suggests that such changes may well underpin the long-term changes in gene expression and metabolism seen in the offspring. However, because of the technical challenges associated with changing the methylation status of a single CpG site in vivo, there is as yet no formal proof that these methylation changes are causal. Although whether causally involved in the development of a disease or a bystander effect of a change in phenotype, the detection of such methylation changes may provide useful markers to identify individuals at increased risk of disease. Consistent with this paradigm, Godfrey et al. reported in two independent cohorts that the methylation status of a single CpG site in the promoter region of the retinoid X receptor A (RXRA) was related positively to childhood adiposity in both boys and girls such that RXRA promoter methylation explained over a fifth of the variance in childhood fat mass (58), while Clarke-Harris et al. demonstrated that the methylation of CpG sites in the promoter of PGC1a in peripheral blood at age 5 to 7 years were predictive of adiposity in the children at ages 9 to 14 (59).
Sex-dependent association of DNA methylation in the coding region of the corticotropin-releasing hormone gene and schizophrenia spectrum disorder
Published in Annals of Human Biology, 2023
Lili Qing, Peng Xiong, Yumei Lu, Hongyan Jiang, Shengjie Nie
Previous studies on CRH methylation have focussed on the promoter region (Mueller and Bale 2008; Elliott et al. 2010; Sterrenburg et al. 2011; Chen et al. 2012; Xu et al. 2014; Jokinen et al. 2018). With ongoing, increasingly in-depth research, some CpG sites have been identified in exons or coding regions; these sites potentially affect promoter activity by modulating transcriptional elongation. In particular, DNA methylation of the coding sequence (CDS) is more effective than that of the promoter in inhibiting gene expression (Hisano et al. 2003; Zhu et al. 2005). For example, CpG methylation in the MCT3 coding region inhibits its expression (Zhu et al. 2005). Testicular germ cell-specific demethylation of the CDSs of the TACT1/actl7b and PDHA2 genes inhibits their expression (Hisano et al. 2003; Pinheiro et al. 2012). Methylation of +10 and +88 CpG sites in the CDS of the MAT1A gene reduces promoter activity by 60% (Tomasi et al. 2012). Based on these results, methylation of CpG sites or CpG islands in the CDS is highly important for the regulation of gene expression. CRH methylation in the CDS of SSD patients has not previously been analysed. The objectives of this study were to determine the methylation status of CpG islands in the CDS of the CRH gene in the SSD population and to explore the relationship between CRH methylation (in the CDS) and SSD.
Dimension-wise sparse low-rank approximation of a matrix with application to variable selection in high-dimensional integrative analyzes of association
Published in Journal of Applied Statistics, 2022
J. C. Poythress, Cheolwoo Park, Jeongyoun Ahn
We apply DSLAM, PMD [30], and SELP-I [25] to the breast cancer data from [13]. The breast cancer data consist of two sets of variables measured from a common set of n = 179 samples. One set contains methylation levels at 1452 CpG sites. The other set contains gene expressions as measured by 511 gene probes. CpG sites are often found in high frequency in the promoter regions of genes. Epigenetic changes such as methylation can affect the expression of the downstream gene. Hypermethylation is associated with gene silencing, while hypomethylation is associated with overexpression. Because the expression of one gene can affect the expression of others, changes in the methylation level at one CpG site can affect the expression levels of an entire group of genes. Moreover, changes at multiple CpG sites may affect the expression of overlapping groups of genes. Thus, the ultimate goal of the analysis is to select a group of CpG sites whose methylation levels are associated with the expression of a group of genes.
Impact of DNA methylation on ADME gene expression, drug disposition, and efficacy
Published in Drug Metabolism Reviews, 2022
Xu Hao, Yuanyuan Li, Jialu Bian, Ying Zhang, Shiyu He, Feng Yu, Yufei Feng, Lin Huang
Recently, emphasis has been placed on epigenetic regulation of ADME gene expression (How Kit et al. 2012). Supplementary Tables 1–4 provided a comprehensive summary of the regulation of DNA methylation on the gene expression of transporters, phase I metabolic enzymes, phase II metabolic enzymes, and nuclear receptors, including the relationship between DNA methylation and gene expression and the CpG sites where DNA methylation occurs. It was found that the degree of DNA methylation of a specific ADME gene was inversely correlated with its gene expression in many studies, but the opposite conclusion was seen in 3 studies, which may be due to the different methylation sites of the same gene being studied. The CpG sites information on the regulatory effect of DNA methylation on selected genes is highlighted below.