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Epigenetic alterations induced by environmental stress associated with metabolic and neurodevelopmental disorders.

ABSTRACT: Epigenetics is a gene regulation mechanism that does not depend on genomic DNA sequences but depends on chemical modification of genomic DNA and histone proteins around which DNA is wrapped. The failure of epigenetic mechanisms is known to cause various congenital disorders. It is also known that the failures of epigenetic mechanisms causes various acquired disorders since epigenetic modifications of the genome (i.e., "epigenome") are more vulnerable to environmental stress, such as malnutrition, environmental chemicals, and mental stress, than the "genome," especially during the early period of life. However, the epigenome has a reversible property since it is based on removable residues on genomic DNA. Thus, environmentally induced epigenomic alterations can be potentially restored. In fact, some medicines, especially for psychiatric diseases, are known to restore an altered epigenome, resulting in the correction of gene expression. Several lines of evidence suggest that environmentally induced epigenomic alterations are not erased completely during gametogenesis, but are transmitted to subsequent generations with disease phenotypes. In accordance with these understandings, I would like to propose the development of epigenomic-based preemptive medicine that consists of the early detection of the developmental origins of diseases using epigenomic signatures and the early intervention that take advantages of the use of epigenomic reversibility.

SUBMITTER: Kubota T

PROVIDER: S-EPMC5804531 | biostudies-other | 2016 Aug

REPOSITORIES: biostudies-other

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Epigenetic alterations induced by environmental stress associated with metabolic and neurodevelopmental disorders.

Kubota Takeo T

Environmental epigenetics 20160808 3

Epigenetics is a gene regulation mechanism that does not depend on genomic DNA sequences but depends on chemical modification of genomic DNA and histone proteins around which DNA is wrapped. The failure of epigenetic mechanisms is known to cause various congenital disorders. It is also known that the failures of epigenetic mechanisms causes various acquired disorders since epigenetic modifications of the genome (i.e., "epigenome") are more vulnerable to environmental stress, such as malnutrition ...[more]

PMID: 29492297

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Project description:Introduction De novo mutations contribute to a large proportion of sporadic psychiatric and developmental disorders, yet the potential role of environmental carcinogens as drivers of causal de novo mutations in neurodevelopmental disorders is poorly studied. Methods To explore environmental mutation vulnerability of disease-associated gene sets, we analyzed publicly available whole genome sequencing datasets of mutations in human induced pluripotent stem cell clonal lines exposed to 12 classes of environmental carcinogens, and human lung cancers from individuals living in highly polluted regions. We compared observed rates of exposure-induced mutations in disease-related gene sets with the expected rates of mutations based on control genes randomly sampled from the genome using exact binomial tests. To explore the role of sequence characteristics in mutation vulnerability, we modeled the effects of sequence length, gene expression, and percent GC content on mutation rates of entire genes and gene coding sequences using multivariate Quasi-Poisson regressions. Results We demonstrate that several mutagens, including radiation and polycyclic aromatic hydrocarbons, disproportionately mutate genes related to neurodevelopmental disorders including autism spectrum disorders, schizophrenia, and attention deficit hyperactivity disorder. Other disease genes including amyotrophic lateral sclerosis, Alzheimer’s disease, congenital heart disease, orofacial clefts, and coronary artery disease were generally not mutated more than expected. Longer sequence length was more strongly associated with elevated mutations in entire genes compared with mutations in coding sequences. Increased expression was associated with decreased coding sequence mutation rate, but not with the mutability of entire genes. Increased GC content was associated with increased coding sequence mutation rates but decreased mutation rates in entire genes. Discussion Our findings support the possibility that neurodevelopmental disorder genetic etiology is partially driven by a contribution of environment-induced germ line and somatic mutations.

Dataset Information

Epigenetic alterations induced by environmental stress associated with metabolic and neurodevelopmental disorders.

Publications

Epigenetic alterations induced by environmental stress associated with metabolic and neurodevelopmental disorders.

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