The Promise of DNA Methylation in Understanding Multigenerational Factors in Autism Spectrum Disorders.
The Promise of DNA Methylation in Understanding Multigenerational Factors in Autism Spectrum Disorders.
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DOI：
10.3389/fgene.2022.831221
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发表时间：
2022
影响因子：
3.7
通讯作者：
LaSalle JM
中科院分区：
文献类型：
--
作者：
Mouat JS;LaSalle JM
自闭症谱系障碍（ASD）是一组以社会互惠和沟通障碍、限制性兴趣和重复性行为为特征的神经发育障碍。大多数ASD病例源于遗传易感性和环境风险因素的共同作用，其相互作用可以通过DNA甲基化等表观遗传机制进行研究。虽然已知父母的各种因素会增加患自闭症的风险，但一些研究表明，祖父母和曾祖父母的因素也可能有所贡献。在动物研究中，妊娠期暴露于某些环境因素，如杀虫剂、药物和社会压力，会增加后代行为表型改变的风险。DNA甲基化、基因表达和染色质可及性的变化通常伴随着这些改变的行为表型，这些变化通常出现在对神经发育很重要的基因或先前与ASD有关的基因中。这些表型和甲基化变化的一种假设机制包括DNA甲基化标记在单个染色体位点上从亲代传递到后代和后代，称为多代表观遗传。或者，亲代的中间代谢表型可能会通过DNA甲基化介导，使原祖父母暴露的风险增加到孙辈患ASD的风险。虽然假设的机制需要进一步的研究，但ASD风险的多代表观遗传学评估的潜力对精准医学具有重要意义，因为该领域试图通过结合遗传、环境和生活方式因素来解决ASD的可变病因和临床症状。在这篇综述中，我们讨论了多代DNA甲基化研究在理解ASD复杂病因学方面的前景。
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairments in social reciprocity and communication, restrictive interests, and repetitive behaviors. Most cases of ASD arise from a confluence of genetic susceptibility and environmental risk factors, whose interactions can be studied through epigenetic mechanisms such as DNA methylation. While various parental factors are known to increase risk for ASD, several studies have indicated that grandparental and great-grandparental factors may also contribute. In animal studies, gestational exposure to certain environmental factors, such as insecticides, medications, and social stress, increases risk for altered behavioral phenotypes in multiple subsequent generations. Changes in DNA methylation, gene expression, and chromatin accessibility often accompany these altered behavioral phenotypes, with changes often appearing in genes that are important for neurodevelopment or have been previously implicated in ASD. One hypothesized mechanism for these phenotypic and methylation changes includes the transmission of DNA methylation marks at individual chromosomal loci from parent to offspring and beyond, called multigenerational epigenetic inheritance. Alternatively, intermediate metabolic phenotypes in the parental generation may confer risk from the original grandparental exposure to risk for ASD in grandchildren, mediated by DNA methylation. While hypothesized mechanisms require further research, the potential for multigenerational epigenetics assessments of ASD risk has implications for precision medicine as the field attempts to address the variable etiology and clinical signs of ASD by incorporating genetic, environmental, and lifestyle factors. In this review, we discuss the promise of multigenerational DNA methylation investigations in understanding the complex etiology of ASD.
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