Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders

Hum Mol Genet. 2014 Mar 15;23(6):1563-78. doi: 10.1093/hmg/ddt547. Epub 2013 Nov 1.


The molecular basis for the majority of cases of autism spectrum disorders (ASD) remains unknown. We tested the hypothesis that ASD have an epigenetic cause by performing DNA methylation profiling of five CpG islands (CGI-1 to CGI-5) in the SHANK3 gene in postmortem brain tissues from 54 ASD patients and 43 controls. We found significantly increased overall DNA methylation (epimutation) in three intragenic CGIs (CGI-2, CGI-3 and CGI-4). The increased methylation was clustered in the CGI-2 and CGI-4 in ∼15% of ASD brain tissues. SHANK3 has an extensive array of mRNA splice variants resulting from combinations of five intragenic promoters and alternative splicing of coding exons. Altered expression and alternative splicing of SHANK3 isoforms were observed in brain tissues with increased methylation of SHANK3 CGIs in ASD brain tissues. A DNA methylation inhibitor modified the methylation of CGIs and altered the isoform-specific expression of SHANK3 in cultured cells. This study is the first to find altered methylation patterns in SHANK3 in ASD brain samples. Our finding provides evidence to support an alternative approach to investigating the molecular basis of ASD. The ability to alter the epigenetic modification and expression of SHANK3 by environmental factors suggests that SHANK3 may be a valuable biomarker for dissecting the role of gene and environment interaction in the etiology of ASD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Brain / metabolism*
  • Brain / pathology
  • Cell Line, Tumor
  • Child Development Disorders, Pervasive / genetics*
  • Child Development Disorders, Pervasive / pathology
  • CpG Islands
  • DNA Methylation
  • Epigenesis, Genetic
  • Exons
  • Gene Expression Regulation
  • Gene-Environment Interaction
  • HEK293 Cells
  • Humans
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Promoter Regions, Genetic
  • Protein Isoforms / metabolism


  • Nerve Tissue Proteins
  • Protein Isoforms
  • SHANK3 protein, human