Autism and DNA methylation

Ciernia AV, LaSalle J. The landscape of DNA methylation amid a perfect storm of autism aetiologies. Nat Rev Neurosci. 2016 May 6. doi: 10.1038/nrn.2016.41. [Epub ahead of print]

Abstract

Increasing evidence points to a complex interplay between genes and the environment in autism spectrum disorder (ASD), including rare de novo mutations in chromatin genes such as methyl-CpG binding protein 2 (MECP2) in Rett syndrome. Epigenetic mechanisms such as DNA methylation act at this interface, reflecting the plasticity in metabolic and neurodevelopmentally regulated gene pathways. Genome-wide studies of gene sequences, gene pathways and DNA methylation are providing valuable mechanistic insights into ASD. The dynamic developmental landscape of DNA methylation is vulnerable to numerous genetic and environmental insults: therefore, understanding pathways that are central to this 'perfect storm' will be crucial to improving the diagnosis and treatment of ASD.

Key points

•The aetiology of autism spectrum disorder is complex: hundreds of genetic variants and various environmental factors have been implicated as risk factors.

•Epigenetic mechanisms such as DNA methylation and chromatin structure are optimally poised at the intersection of genes and environment in autism aetiologies.

•DNA methylation includes multiple modification types, some of which are specifically enriched in the nervous system.

•The association of DNA methylation with gene expression and the dynamics of modification changes during brain development depend on genomic context.

•DNA-methylation patterns are highly dynamic across the lifespan, with the biggest changes occurring around implantation and in the transition between fetal to early postnatal life.

•Alterations in DNA methylation have been observed by both candidate gene and genomic studies of the post-mortem brain in autism. Future investigations of the autistic brain and surrogate tissues using larger sample sizes and whole-genome sequencing approaches hold promise for improved understanding and potential molecular diagnosis of autism risk.

From the article:

Given that most cases of ASD result from a combination of genetic risk and environmental exposures, alterations in DNA methylation serve as an attractive mechanism to link environmental perturbations to lifelong changes in brain function and behaviour. DNA methylation may have various roles in brain development, including directly affecting gene expression by recruiting specific DNA methyl-binding proteins or serving as a mark of previous transcriptional events that are adaptive in poising genomic regions for future events. Examining DNA methylation in the context of developmental gene expression, other epigenomic markers of chromatin state and cell type can predict functional impact. How DNA methylation affects brain function is also inherently tied to genetic variation in transcription factors, methyl-binding proteins and other regulatory proteins and distal DNA regions. The combination of specific inherited genetic variants may make some individuals more susceptible to environmental risk factors such as chemical exposures, maternal infection or low folate levels. Individuals harbouring CNVs or single-nucleotide variants that affect chromatin and synaptic genes might also be especially sensitive to environmental perturbations. Given the widespread and highly dynamic changes in DNA methylation that occur in early fetal life, this time point in development may be particularly vulnerable to the cumulative impact of genetic and environmental risk factors.

Testing the causal relationship between DNA-methylation changes and altered brain development is difficult. DNA methylation is likely to be both a cause and consequence of the developmental regulation of gene expression and occurs in the context of other epigenomic mechanisms of regulation, such as histone modifications. Consequently, differences in methylation at any given point in development may or may not provide mechanistic information on the current state of neurodevelopment. For example, altered brain development caused by a genetic or environmental perturbation may indirectly affect DNA methylation as the brain attempts to compensate for suboptimal conditions. So far, there is only limited evidence of altered DNA-methylation patterns in ASD brain samples, but the levels of methyl donors available to the developing fetus during gestation are related to ASD risk. Although this is hardly causal evidence, it does suggest that supplements containing methyl donors taken before conception may provide some protection against ASD by mitigating the perfect storm of risk factors and aberrant DNA methylation in genetically susceptible individuals.

Courtesy of Doximity