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Chromatin modifications in metabolic disease: Potential mediators of long‐term disease risk

Focus Article

Kevin R. Costello, Dustin E. Schones

Published Online: Jan 25 2018

DOI: 10.1002/wsbm.1416

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Metabolic diseases such as obesity and diabetes are complex diseases resulting from multiple genetic and environmental factors, such as diet and activity levels. These factors are well known contributors to the development of metabolic diseases. One manner by which environmental factors can influence metabolic disease progression is through modifications to chromatin. These modifications can lead to altered gene regulatory programs, which alters disease risk. Furthermore, there is evidence that parents exposed to environmental factors can influence the metabolic health of offspring, especially if exposures are during intrauterine growth periods. In this review, we outline the evidence that chromatin modifications are associated with metabolic diseases, including diabetes and obesity. We also consider evidence that these chromatin modifications can lead to long‐term disease risk and contribute to disease risk for future generations. This article is categorized under: Biological Mechanisms > Metabolism Developmental Biology > Developmental Processes in Health and Disease Physiology > Organismal Responses to Environment

Chromatin modifications associated with “permissive” or “repressive” environments. Modifications to histone tails and DNA methylation are associated with “repressive” states with condensed chromatin or “permissive” state of more accessible chromatin. Red balls, DNA methylation; purple balls, repressive histone modifications; green balls, active histone modifications; yellow globes, histone proteins; blue globes, histone variants

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Small RNA‐mediated regulation of gene expression from parental small RNA. Parental small RNAs, in a function independent of the genomic information in sperm, have been shown to transmit phenotypes to offspring. sRNAs can complex to RNA transcripts and induce degradation. Alternatively, sRNAs could bind to actively transcribed RNA in the genome and cause the recruitment of DNA and histone modifying proteins. This could lead to targeted heterochromatin formation in the genome

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Intergenerational versus transgenerational inheritance. Epigenetic inheritance in mice can be defined by the number of generations the phenotype penetrates. Maternal effects are changes to the offspring caused as a result of changes in the womb, that is, starvation or altered metabolite intake. The children born after these conditions with altered epigenetic structure are the F0 generation. The F0 generation can also be generated if there is some altering effect, that is, obesogenic diet, that alter the germs cells of an individual. If the phenotype is successfully passed on from the F0 generation to their offspring, the F1 generation, the phenotype is viewed as an intergenerational phenotype. If the phenotype is successfully transferred from the F1 generation to the F2 generation and beyond, the phenotype is viewed as a transgenerational phenotype

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Epigenetics and metabolic memory. The phenomenon of metabolic memory is the observation that complications due to metabolic disease can persist even after metabolic disease is mitigated. Epigenetic modifications are an attractive candidate for mediating this phenomenon

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Metabolites and chromatin structure. Metabolites are required by many chromatin modifying proteins. S‐adenosyl methionine (SAM) is required by DNA methyltransferases (DNMTs), as well as histone methyltransferases (HMTs) to add a methyl group to DNA or histone tails (Rea et al., ). The metabolites fumartate, succinate and α‐ketogluterate regulate Ten‐eleven translocase (TET) proteins (Klose, Kallin, & Zhang, ). TETs are responsible for the removal of methyl groups from DNA. Flavin adenine dinucleotide (FAD) regulates lysine demethylase (KDM) to regulate the removal of methyl groups from histones. Acetyl‐CoA is required for the addition of acetyl groups to histones by histone acetyl transferases (HATs) (Galdieri & Vancura, ). Nicotinamide adenine dinucleotide (NADH) interacts with Sirtuins to facilitate acetyl group removal by histone deacetylases (HDACs) (Ions et al., ). ATP is a required substrate for serine/threonine kinase (ATM) phosphorylation of histones (Banerjee, Bennion, Goldberg, & Allen, ), which is removed by protein serine/threonine phosphatases (PSPs)

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Developmental epigenetic reprograming. There are waves of genome‐wide demethylation followed by the establishment of methylation in primordial germ cells (PGCs) and following fertilization. The vast majority of the genome undergoes this loss of methylation. However, a group of evolutionarily young transposable elements, referred to as “escapees,” avoid the demethylation

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