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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.00907

Epigenetic delay in the neurodevelopmental trajectory of DNA methylation states in autism spectrum disorders

  • 1Department of Native Hawaiian Health, John A. Burns School of Medicine, University of Hawaii at Mānoa, United States
  • 2Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Mānoa, United States
  • 3University of Hawaii Cancer Center, United States
  • 4Department of Clinical and Translational Research, Medical Center, University of Rochester, United States
  • 5University of Hawaii at Manoa, United States
  • 6Bekesy Neurobiology Laboratory, Pacific Biosciences Research Center, University of Hawaii at Manoa, United States

Autism spectrum disorders (ASD) are hypothesized to originate in utero from perturbations in neural stem cell niche regions of the developing brain. Dynamic epigenetic processes including DNA methylation are integral to coordinating typical brain development. However, the extent and consequences of alterations to DNA methylation states in neural stem cell compartments in ASD are unknown. Here, we report significant DNA methylation defects in the subventricular zone (SVZ) of the lateral ventricles from postmortem brain of seventeen autism-diagnosed compared to seventeen age and gender-matched typically developing individuals. Both array- and sequencing-based genome-wide methylome analyses independently revealed that these alterations were preferentially targeted to intragenic and bivalently modified chromatin domains of genes predominately involved in neurodevelopment, which associated with aberrant pre-mRNA splicing events of ASD-relevant genes. Integrative analysis of our ASD and typically developing postmortem brain methylome datasets with that from fetal brain at different neurodevelopmental stages revealed that the methylation states of differentially methylated loci associated with ASD remarkably resemble the methylation states at earlier time points in fetal brain development. This observation was confirmed using additional methylome datasets from three other brain regions. Altogether, these findings implicate an epigenetic delay in the trajectory of normal DNA methylation states during the course of brain development that may consequently lead to deleterious transcriptomic events in ASD and support the hypothesis of an early developmental origin of ASD.

Keywords: Autism (ASD), DNA methyaltion, Brain, Epigenetic abnormalities, RNA-Seq

Received: 12 May 2019; Accepted: 28 Aug 2019.

Copyright: © 2019 Corley, Vargas-Maya, Pang, Lum-Jones, Li, Khadka, Sultana, Blanchard and Maunakea. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Alika Maunakea, Department of Native Hawaiian Health, John A. Burns School of Medicine, University of Hawaii at Mānoa, Honolulu, 96813, Hawaii, United States,