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The landscape of DNA methylation amid a perfect storm of autism aetiologies

Nature Reviews Neuroscience volume 17, pages 411–423 (2016)Cite this article

Subjects

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.

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.

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Figure 1: Types of DNA methylation in the mammalian brain.
Figure 2: The landscape of DNA methylation in relation to gene expression.
Figure 3: DNA methylation landscape across development.

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Acknowledgements

The authors thank D. Yasui, K. Dunaway and A. Nord for critical reading of the manuscript. Ongoing support for this research is supported by the US National Institute of Neurological Disorders and Stroke (grants R01NS081913 and R01NS076263), the US National Institute of Environmental Health Sciences (grant R01ES021707), the US Department of Defense (grant W81XWH-12-1-0491) and the US National Institute of Mental Health (grant T32MH073124-06).

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  1. Medical Microbiology and Immunology, MIND Institute, Genome Center, University of California, Davis, 95616, California, USA

    Annie Vogel Ciernia & Janine LaSalle

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  1. Annie Vogel Ciernia
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Correspondence to Janine LaSalle.

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PowerPoint slides

Glossary

CpG

Cytosine 5′ of guanine, where the 'p' stands for the phosphate.

5-methylcytosine

(5mC). A cytosine base with a methyl group (CH3) in the 5′ position.

CpG islands

Short (< 1 kb) regions in mammalian genomes with the highest density of CpG sites.

5-hydroxymethylcytosine

(5hmC). A cytosine base with a hydroxymethyl (-CH2-OH) group in the 5′ position.

CpH

A cytosine followed by either adenine (CpA), cytosine (CpC) or thymine (CpT), where the 'p' stands for the phosphate

Ten-eleven translocase

(TET). The three TET enzymes, TET1, TET2 and TET3, are methylcytosine dioxygenases that convert 5-methylcytosine to 5-hydroxymethylcytosine.

Gene body

The genomic region extending from the transcription start site to the transcription end site.

Methyl-binding domain

(MBD). A protein domain structure with a higher affinity to methylated DNA than to unmethylated DNA. The MBD family of proteins includes methyl-CpG binding protein 2.

Differentially methylated regions

(DMRs). Short clusters of CpG sites in regions showing significant differences in methylation between stages or samples, defined bioinformatically.

Partially methylated domains

(PMDs). Large genomic regions in the mammalian genome that are characterized by lower than 70% 5-methylcytosine-guanine (5mCG). PMDs are found in 30–50% of the genome in preimplantation embryos, the placenta and most solid tumours. They are characterized by lower or more-variable transcript levels, repressive histone marks and nuclear lamina localization.

Inner cell mass

(ICM). The cells in the blastocyst of the preimplantation embryo that become fetal tissues.

Primordial germ cells

(PGCs). The embryonic lineage of cells that migrate to the genital ridge as precursors of the germline cells of the next generation (spermatagonia and oocytes).

Methylenetetrahydrofolate reductase

(MTHFR). An enzyme in the one-carbon metabolism cycle that supplies methyl groups for DNA-methylation reactions. A common polymorphism in the MTHFR gene encodes a less-efficient enzyme and is a risk factor for neural tube defects and autism.

DNA methylation valleys

(DMVs). Regions of low methylation that are >5 kb in length and are found in most cell types. They can show differences in developmental methylation between fetal and adult tissues.

Induced pluripotent stem cells

(iPSCs). Adult somatic cells that are genetically reprogrammed in vitro to produce an embryonic stem cell-like state of pluripotency. iPSCs can then be differentiated into a number of different cell types.

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Ciernia, A., LaSalle, J. The landscape of DNA methylation amid a perfect storm of autism aetiologies. Nat Rev Neurosci 17, 411–423 (2016). https://doi.org/10.1038/nrn.2016.41

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