1932

Abstract

The prevalence of autism spectrum disorder (ASD) has been increasing steadily over the last 20 years; however, the molecular basis for the majority of ASD cases remains unknown. Recent advances in next-generation sequencing and detection of DNA modifications have made methylation-dependent regulation of transcription an attractive hypothesis for being a causative factor in ASD etiology. Evidence for abnormal DNA methylation in ASD can be seen on multiple levels, from genetic mutations in epigenetic machinery to loci-specific and genome-wide changes in DNA methylation. Epimutations in DNA methylation can be acquired throughout life, as global DNA methylation reprogramming is dynamic during embryonic development and the early postnatal period that corresponds to the peak time of synaptogenesis. However, technical advances and causative evidence still need to be established before abnormal DNA methylation and ASD can be confidently associated.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-120417-091431
2019-01-27
2024-12-10
Loading full text...

Full text loading...

/deliver/fulltext/med/70/1/annurev-med-120417-091431.html?itemId=/content/journals/10.1146/annurev-med-120417-091431&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  American Psychiatric Association 2013. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 Washington, DC: Am. Psychiatr. Assoc
    [Google Scholar]
  2. 2.  Baio J, Wiggins L, Christensen DL et al. 2018. Prevalence of autism spectrum disorder among children aged 8 years—Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2014. MMWR Surveill. Summ. 67:1–23
    [Google Scholar]
  3. 3.  Folstein SE, Rosen-Sheidley B 2001. Genetics of autism: complex aetiology for a heterogeneous disorder. Nat. Rev. Genet. 2:943–55
    [Google Scholar]
  4. 4.  Jiang YH, Wang Y, Xiu X et al. 2014. Genetic diagnosis of autism spectrum disorders: the opportunity and challenge in the genomics era. Crit. Rev. Clin. Lab. Sci. 51:249–62
    [Google Scholar]
  5. 5.  Willsey AJ, State MW 2015. Autism spectrum disorders: from genes to neurobiology. Curr. Opin. Neurobiol. 30C:92–99
    [Google Scholar]
  6. 6.  Iossifov I, O'Roak BJ, Sanders SJ et al. 2014. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515:216–21
    [Google Scholar]
  7. 7.  De Rubeis S, He X, Goldberg AP et al. 2014. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515:209–15
    [Google Scholar]
  8. 8.  Gaugler T, Klei L, Sanders SJ et al. 2014. Most genetic risk for autism resides with common variation. Nat. Genet. 46:881–85
    [Google Scholar]
  9. 9.  Yu TW, Chahrour MH, Coulter ME et al. 2013. Using whole-exome sequencing to identify inherited causes of autism. Neuron 77:259–73
    [Google Scholar]
  10. 10.  Buxbaum JD, Daly MJ, Devlin B et al. 2012. The autism sequencing consortium: large-scale, high-throughput sequencing in autism spectrum disorders. Neuron 76:1052–56
    [Google Scholar]
  11. 11.  Neale BM, Kou Y, Liu L et al. 2012. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485:242–45
    [Google Scholar]
  12. 12.  O'Roak BJ, Deriziotis P, Lee C et al. 2011. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43:585–89
    [Google Scholar]
  13. 13.  O'Roak BJ, Vives L, Girirajan S et al. 2012. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246–50
    [Google Scholar]
  14. 14.  Sanders SJ, Murtha MT, Gupta AR et al. 2012. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–41
    [Google Scholar]
  15. 15.  Iossifov I, Ronemus M, Levy D et al. 2012. De novo gene disruptions in children on the autistic spectrum. Neuron 74:285–99
    [Google Scholar]
  16. 16.  Tran NQV, Miyake K 2017. Neurodevelopmental disorders and environmental toxicants: epigenetics as an underlying mechanism. Int. J. Genom. 2017:7526592
    [Google Scholar]
  17. 17.  Keil KP, Lein PJ 2016. DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders?. Environ. Epigenet. 2:1–15
    [Google Scholar]
  18. 18.  Bird A 2007. Perceptions of epigenetics. Nature 447:396–98
    [Google Scholar]
  19. 19.  Henikoff S, Greally JM 2016. Epigenetics, cellular memory and gene regulation. Curr. Biol. 26:R644–48
    [Google Scholar]
  20. 20.  Allis CD, Jenuwein T 2016. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 17:487–500
    [Google Scholar]
  21. 21.  de la Torre-Ubieta L, Stein JL, Won H et al. 2018. The dynamic landscape of open chromatin during human cortical neurogenesis. Cell 172:289–304
    [Google Scholar]
  22. 22.  Lister R, Mukamel EA, Nery JR et al. 2013. Global epigenomic reconfiguration during mammalian brain development. Science 341:1237905
    [Google Scholar]
  23. 23.  Bale TL 2015. Epigenetic and transgenerational reprogramming of brain development. Nat. Rev. Neurosci. 16:332–44
    [Google Scholar]
  24. 24.  Madrid A, Papale LA, Alisch RS 2016. New hope: the emerging role of 5-hydroxymethylcytosine in mental health and disease. Epigenomics 8:981–91
    [Google Scholar]
  25. 25.  Jiang YH, Bressler J, Beaudet AL 2004. Epigenetics and human disease. Annu. Rev. Genom. Hum. Genet. 5:479–510
    [Google Scholar]
  26. 26.  Brookes E, Shi Y 2014. Diverse epigenetic mechanisms of human disease. Annu. Rev. Genet. 48:237–68
    [Google Scholar]
  27. 27.  Lyko F 2018. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat. Rev. Genet. 19:81–92
    [Google Scholar]
  28. 28.  Wu X, Zhang Y 2017. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat. Rev. Genet. 18:517–34
    [Google Scholar]
  29. 29.  Bird A 2002. DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21
    [Google Scholar]
  30. 30.  Mentch SJ, Locasale JW 2016. One-carbon metabolism and epigenetics: understanding the specificity. Ann. N. Y. Acad. Sci. 1363:91–98
    [Google Scholar]
  31. 31.  Chen T, Li E 2004. Structure and function of eukaryotic DNA methyltransferases. Curr. Top. Dev. Biol. 60:55–89
    [Google Scholar]
  32. 32.  Cortellino S, Xu J, Sannai M et al. 2011. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 146:67–79
    [Google Scholar]
  33. 33.  Wu SC, Zhang Y 2010. Active DNA demethylation: many roads lead to Rome. Nat. Rev. Mol. Cell Biol. 11:607–20
    [Google Scholar]
  34. 34.  Deaton AM, Bird A 2011. CpG islands and the regulation of transcription. Genes Dev 25:1010–22
    [Google Scholar]
  35. 35.  Yin Y, Morgunova E, Jolma A et al. 2017. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 356:eaaj2239
    [Google Scholar]
  36. 36.  Lorincz MC, Dickerson DR, Schmitt M et al. 2004. Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nat. Struct. Mol. Biol. 11:1068–75
    [Google Scholar]
  37. 37.  Luo GZ, Blanco MA, Greer EL et al. 2015. DNA N(6)-methyladenine: a new epigenetic mark in eukaryotes?. Nat. Rev. Mol. Cell Biol. 16:705–10
    [Google Scholar]
  38. 38.  Feng J, Chang H, Li E et al. 2005. Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J. Neurosci. Res. 79:734–46
    [Google Scholar]
  39. 39.  Feng J, Zhou Y, Campbell SL et al. 2010. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat. Neurosci. 13:423–30
    [Google Scholar]
  40. 40.  Ko YG, Nishino K, Hattori N et al. 2005. Stage-by-stage change in DNA methylation status of Dnmt1 locus during mouse early development. J. Biol. Chem. 280:9627–34
    [Google Scholar]
  41. 41.  Wossidlo M, Nakamura T, Lepikhov K et al. 2011. 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat. Commun. 2:241
    [Google Scholar]
  42. 42.  Szwagierczak A, Bultmann S, Schmidt CS et al. 2010. Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA. Nucleic Acids Res 38:e181
    [Google Scholar]
  43. 43.  Morgan HD, Santos F, Green K et al. 2005. Epigenetic reprogramming in mammals. Hum. Mol. Genet. 14:Spec. No. 1R47–58
    [Google Scholar]
  44. 44.  Reik W, Walter J 2001. Genomic imprinting: parental influence on the genome. Nat. Rev. Genet. 2:21–32
    [Google Scholar]
  45. 45.  Gu TP, Guo F, Yang H et al. 2011. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477:606–10
    [Google Scholar]
  46. 46.  von Meyenn F, Iurlaro M, Habibi E et al. 2016. Impairment of DNA methylation maintenance is the main cause of global demethylation in naive embryonic stem cells. Mol. Cell 62:848–61
    [Google Scholar]
  47. 47.  Oey H, Whitelaw E 2014. On the meaning of the word ‘epimutation’. Trends Genet 30:519–20
    [Google Scholar]
  48. 48.  Horsthemke B 2006. Epimutations in human disease. Curr. Top. Microbiol. Immunol. 310:45–59
    [Google Scholar]
  49. 49.  Jiang Y, Tsai TF, Bressler J et al. 1998. Imprinting in Angelman and Prader-Willi syndromes. Curr. Opin. Genet. Dev. 8:334–42
    [Google Scholar]
  50. 50.  Penagarikano O, Mulle JG, Warren ST 2007. The pathophysiology of fragile X syndrome. Annu. Rev. Genom. Hum. Genet. 8:109–29
    [Google Scholar]
  51. 51.  Lister R, Pelizzola M, Dowen RH et al. 2009. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–22
    [Google Scholar]
  52. 52.  Spiers H, Hannon E, Schalkwyk LC et al. 2017. 5-hydroxymethylcytosine is highly dynamic across human fetal brain development. BMC Genom 18:738
    [Google Scholar]
  53. 53.  Pidsley R, Viana J, Hannon E et al. 2014. Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia. Genome Biol 15:483
    [Google Scholar]
  54. 54.  Spiers H, Hannon E, Schalkwyk LC et al. 2015. Methylomic trajectories across human fetal brain development. Genome Res 25:338–52
    [Google Scholar]
  55. 55.  Jirtle RL, Skinner MK 2007. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet. 8:253–62
    [Google Scholar]
  56. 56.  Abrahams BS, Arking DE, Campbell DB et al. 2013. SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs). Mol. Autism 4:36
    [Google Scholar]
  57. 57. Deciphering Developmental Disorders Study. 2015. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519:223–28
    [Google Scholar]
  58. 58.  Zhubi A, Chen Y, Dong E et al. 2014. Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum. Transl. Psychiatry 4:e349
    [Google Scholar]
  59. 59.  Cukier HN, Rabionet R, Konidari I et al. 2010. Novel variants identified in methyl-CpG-binding domain genes in autistic individuals. Neurogenetics 11:291–303
    [Google Scholar]
  60. 60.  Talkowski ME, Mullegama SV, Rosenfeld JA et al. 2011. Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. Am. J. Hum. Genet. 89:551–63
    [Google Scholar]
  61. 61.  Jiang YH, Sahoo T, Michaelis RC et al. 2004. A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A. Am. J. Med. Genet. A 131:1–10
    [Google Scholar]
  62. 62.  Nagarajan RP, Patzel KA, Martin M et al. 2008. MECP2 promoter methylation and X chromosome inactivation in autism. Autism Res 1:169–78
    [Google Scholar]
  63. 63.  Wong CC, Meaburn EL, Ronald A et al. 2014. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol. Psychiatry 19:495–503
    [Google Scholar]
  64. 64.  Gregory SG, Connelly JJ, Towers AJ et al. 2009. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med 7:62
    [Google Scholar]
  65. 65.  Labouesse MA, Dong E, Grayson DR et al. 2015. Maternal immune activation induces GAD1 and GAD2 promoter remodeling in the offspring prefrontal cortex. Epigenetics 10:1143–55
    [Google Scholar]
  66. 66.  Hogart A, Leung KN, Wang NJ et al. 2009. Chromosome 15q11–13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number. J. Med. Genet. 46:86–93
    [Google Scholar]
  67. 67.  Lintas C, Sacco R, Persico AM 2016. Differential methylation at the RELN gene promoter in temporal cortex from autistic and typically developing post-puberal subjects. J. Neurodev. Disord. 8:18
    [Google Scholar]
  68. 68.  Homs A, Codina-Sola M, Rodriguez-Santiago B et al. 2016. Genetic and epigenetic methylation defects and implication of the ERMN gene in autism spectrum disorders. Transl. Psychiatry 6:e855
    [Google Scholar]
  69. 69.  James SJ, Shpyleva S, Melnyk S et al. 2014. Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum. Transl. Psychiatry 4:e460
    [Google Scholar]
  70. 70.  Zhu L, Wang X, Li XL et al. 2014. Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders. Hum. Mol. Genet. 23:1563–78
    [Google Scholar]
  71. 71.  Maunakea AK, Chepelev I, Cui K et al. 2013. Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res 23:1256–69
    [Google Scholar]
  72. 72.  Neri F, Rapelli S, Krepelova A et al. 2017. Intragenic DNA methylation prevents spurious transcription initiation. Nature 543:72–77
    [Google Scholar]
  73. 73.  Lev Maor G, Yearim A, Ast G 2015. The alternative role of DNA methylation in splicing regulation. Trends Genet 31:274–80
    [Google Scholar]
  74. 74.  Quesnel-Vallieres M, Dargaei Z, Irimia M et al. 2016. Misregulation of an activity-dependent splicing network as a common mechanism underlying autism spectrum disorders. Mol. Cell 64:1023–34
    [Google Scholar]
  75. 75.  Irimia M, Weatheritt RJ, Ellis JD et al. 2014. A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell 159:1511–23
    [Google Scholar]
  76. 76.  Li Q, Lee JA, Black DL 2007. Neuronal regulation of alternative pre-mRNA splicing. Nat. Rev. Neurosci. 8:819–31
    [Google Scholar]
  77. 77.  Vuong CK, Black DL, Zheng S 2016. The neurogenetics of alternative splicing. Nat. Rev. Neurosci. 17:265–81
    [Google Scholar]
  78. 78.  Andrews SV, Ellis SE, Bakulski KM et al. 2017. Cross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder. Nat. Commun. 8:1011
    [Google Scholar]
  79. 79.  Tsang SY, Ahmad T, Mat FW et al. 2016. Variation of global DNA methylation levels with age and in autistic children. Hum. Genom. 10:31
    [Google Scholar]
  80. 80.  Feinberg JI, Bakulski KM, Jaffe AE et al. 2015. Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort. Int. J. Epidemiol. 44:1199–210
    [Google Scholar]
  81. 81.  Schroeder DI, Schmidt RJ, Crary-Dooley FK et al. 2016. Placental methylome analysis from a prospective autism study. Mol. Autism 7:51
    [Google Scholar]
  82. 82.  Nardone S, Sams DS, Reuveni E et al. 2014. DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Transl. Psychiatry 4:e433
    [Google Scholar]
  83. 83.  Nardone S, Sams DS, Zito A et al. 2017. Dysregulation of cortical neuron DNA methylation profile in autism spectrum disorder. Cereb. Cortex 27:5739–54
    [Google Scholar]
  84. 84.  Ladd-Acosta C, Hansen KD, Briem E et al. 2014. Common DNA methylation alterations in multiple brain regions in autism. Mol. Psychiatry 19:862–71
    [Google Scholar]
  85. 85.  Dunaway KW, Islam MS, Coulson RL et al. 2016. Cumulative impact of polychlorinated biphenyl and large chromosomal duplications on DNA methylation, chromatin, and expression of autism candidate genes. Cell Rep 17:3035–48
    [Google Scholar]
  86. 86.  Ellis SE, Gupta S, Moes A et al. 2017. Exaggerated CpH methylation in the autism-affected brain. Mol. Autism 8:6
    [Google Scholar]
  87. 87.  Hannon E, Schendel D, Ladd-Acosta C et al. 2018. Elevated polygenic burden for autism is associated with differential DNA methylation at birth. Genome Med 10:19
    [Google Scholar]
  88. 88.  Cheng Y, Li Z, Manupipatpong S et al. 2018. 5-Hydroxymethylcytosine alterations in the human postmortem brains of autism spectrum disorder. Hum. Mol. Genet. 17:2955–64
    [Google Scholar]
  89. 89.  Wang T, Pan Q, Lin L et al. 2012. Genome-wide DNA hydroxymethylation changes are associated with neurodevelopmental genes in the developing human cerebellum. Hum. Mol. Genet. 21:5500–10
    [Google Scholar]
  90. 90.  Waterland RA, Jirtle RL 2003. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol. Cell. Biol. 23:5293–300
    [Google Scholar]
  91. 91.  Weaver IC, Cervoni N, Champagne FA et al. 2004. Epigenetic programming by maternal behavior. Nat. Neurosci. 7:847–54
    [Google Scholar]
  92. 92.  Dolinoy DC, Huang D, Jirtle RL 2007. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. PNAS 104:13056–61
    [Google Scholar]
  93. 93.  Ruiz-Hernandez A, Kuo CC, Rentero-Garrido P et al. 2015. Environmental chemicals and DNA methylation in adults: a systematic review of the epidemiologic evidence. Clin. Epigenet. 7:55
    [Google Scholar]
  94. 94.  Sharp GC, Salas LA, Monnereau C et al. 2017. Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium. Hum. Mol. Genet. 26:4067–85
    [Google Scholar]
  95. 95.  Maccani JZ, Maccani MA 2015. Altered placental DNA methylation patterns associated with maternal smoking: current perspectives. Adv. Genom. Genet. 2015:205–14
    [Google Scholar]
  96. 96.  McGowan PO, Sasaki A, D'Alessio AC et al. 2009. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat. Neurosci. 12:342–48
    [Google Scholar]
  97. 97.  Won H, de la Torre-Ubieta L, Stein JL et al. 2016. Chromosome conformation elucidates regulatory relationships in developing human brain. Nature 538:523–27
    [Google Scholar]
  98. 98.  Parikshak NN, Luo R, Zhang A et al. 2013. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155:1008–21
    [Google Scholar]
  99. 99.  Onuchic V, Lurie E, Carrero I et al. 2018. Allele-specific epigenome maps reveal sequence-dependent stochastic switching at regulatory loci. Science 23:aar3146
    [Google Scholar]
  100. 100.  Schmitz RJ, Schultz MD, Lewsey MG et al. 2011. Transgenerational epigenetic instability is a source of novel methylation variants. Science 334:369–73
    [Google Scholar]
/content/journals/10.1146/annurev-med-120417-091431
Loading
/content/journals/10.1146/annurev-med-120417-091431
Loading

Data & Media loading...

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error