Epigenetic Mechanisms in Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social interactions, language deficits, as well as restrictive or repetitive behaviors. ASD is clinically heterogeneous with a complex etiopathogenesis which may be conceptualized as a dynamic interplay between heterogeneous environmental cues and predisposing genetic factors involving complex epigenetic mechanisms. Inherited and de novo copy number variants provide novel information regarding genes contributing to ASD. Epigenetic marks are stable, yet potentially reversible, chromatin modifications that alter gene expression profiles by locally changing the degree of nucleosomal compaction, thereby opening or closing promoter access to the transcriptional machinery. Here, we review progress on studies designed to provide a better understanding of how epigenetic mechanisms impact transcriptional programs operative in the brain that contribute to ASD.

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by symptoms that include deficits in social interactions, under-developed communication skills, and restrictive or repetitive behaviors. Population-wide prevalence of ASD is approximately 1% and it is more common in males than females (4:1) (Abrahams and Geschwind, 2008, Bailey et al., 1995, Baron-Cohen et al., 2009, O'Roak and State, 2008, Veenstra-Vanderweele and Cook, 2004). ASD is clinically and etiologically heterogeneous with many of the diagnostic symptoms showing considerable variation in severity. Approximately 5–20% of cases involve large effect de novo copy number variants. Genome-wide association studies are frequently used to compare the frequencies of single-nucleotide polymorphisms (SNPs) in ASD DNA samples. While no replicable single SNP variants have been identified, the cumulative contributions of inherited genetic variation over many small effect loci has recently been estimated to be as high as 40% (Klei et al., 2012).

Microarrays are used extensively to map the large number of copy number variants (CNVs) in the human population (Cook & Scherer, 2008). These mutations are variable in length and are either inherited or arise due to spontaneous (de novo) duplication, insertion, or deletion across the genome. Given the phenotypic overlap, it is not surprising that CNVs tend to be more frequent in patients with psychiatric disorders of neurodevelopmental origin such as intellectual disability/mental retardation (including patients with learning deficits), schizophrenia (SZ), and ASD (De Lacy and King, 2013, Guilmatre et al., 2009). Various tests of cognitive function show that control subjects known to be carrying CNVs that confer risk for either ASD or SZ test in terms of cognitive performance at a level intermediate between SZ and population controls (Stefansson et al., 2014). Moreover, CNVs do not all affect the same cognitive domains and vary considerably from one mutation to another (Stefansson et al., 2014). Two important goals of clinical geneticists are (1) to improve CNV detection and (2) to improve the phenotyping of CNV carriers that also exhibit psychotic symptoms. Recent analyses of topological networks derived from ASD CNVs and mouse functional genomics are being used to unveil highly detailed ASD-associated interaction networks that allow testing of novel hypotheses regarding cellular signaling and biological function (Noh et al., 2013, Veenstra-Vanderweele and Blakely, 2012).

One of the more frequently observed CNVs associated with high penetrance for ASD is the maternal duplication of chromosome 15q11-13. A second well-known CNV is a 600 kb microdeletion/microinsertion at chromosome 16p11.2 which occurs in some 1% of sporadic ASD cases (Cook & Scherer, 2008). Syndromic ASD, which occurs in 10% of cases, is observed when diagnostic behaviors are comorbid with a recognized syndrome. Some of the monogenic (syndromic) conditions associated with the ASD phenotype are Rett (RTT) syndrome (MECP2 gene; Amir et al., 1999), fragile X syndrome (FXS, FMR1), tuberous sclerosis (TSC1 and TSC2; Wiznitzer, 2004), neurofibromatosis (NF1), Timothy syndrome (CACNA1; Splawski et al., 2006), and cortical dysplasia–focal epilepsy syndrome (CNTNAP2; Strauss et al., 2006). Each of the above conditions exhibits phenotypes that overlap with ASD and hence offer important insight into how the corresponding genes contribute to pathogenesis.

Several twin studies have reported concordance rates between MZ twins at between 70% and 90%, while DZ twin concordance rates vary from 6% to 10%, with a more than 20-fold increased risk for siblings (Bailey et al., 1995, Eapen et al., 2013, Steffenburg et al., 1989). Phenotypic discordance between MZ twins is often associated with de novo mutations (Hallmayer et al., 2011, Zafeiriou et al., 2013) and numerous nonshared environmental factors including in utero growth restrictions (these include uneven blood supply, placental dysfunction, differential allelic expression, etc., and stochastic noise (Czyz, Morahan, Ebers, & Ramagopalan, 2012)). In addition, numerous pre and perinatal factors, e.g., low birth weight and prematurity, are among multiple factors associated with higher risk of ASD (Gardener, Spiegelman, & Buka, 2011). These observations are consistent with the hypothesis that environmental factors contribute to ASD and support an epigenetic component in phenotypic variation. This variation may be the consequence of parental allelic origin (imprinting) or the effects of DNA methylation/hydroxymethylation on the epigenome. Moreover, epigenetic factors also manifest at multiple additional levels including histone tail modifications, variations in methyl DNA-binding proteins, etc. Recently, there has been a growth in interest in studies of the involvement of epigenetic mechanisms in the pathophysiology of ASD. The overlapping phenotypic features of ASD that are shared with related neurodevelopmental disorders may be explained through altered gene expression profiles filtered through various epigenetic mechanisms (Lasalle, 2013, Miyauchi and Voineagu, 2013, Voineagu et al., 2011). In other words, as researchers begin to compare the gene expression networks between different neurodevelopmental disorders, differences in specific biological pathways and brain regions that reflect the phenotypes associated with each disease should become apparent (Hoerder-Suabedissen et al., 2013, Parikshak et al., 2013, Willsey et al., 2013). In summary, one plausible mechanistic approach to understanding the etiology of ASD supports the concept that environmental/epigenetic perturbations incurred during early nervous system development operate on and enhance the contributions of a large number of susceptibility genes identified as either inherited or de novo mutations which themselves may influence epigenetic regulation (see Fig. 6.1). Here, we summarize progress on epigenetic mechanisms operative in brain with the goal of understanding the distinct or overlapping features of these mechanisms in the etiopathogenesis of ASD. We provide a basic overview of histone modifications, DNA methylation, and hydroxymethylation before proceeding onto subsequent topics. While we have not discussed the impact of microRNAs (miRNAs), long noncoding RNAs (ncRNAs), and enhancer RNAs on transcriptional regulation, there have been several recent reviews on these subjects (Melios and Sur, 2012, Peschansky and Wahlestedt, 2014, Roberts et al., 2014, Velmeshev et al., 2013, Wilkinson and Campbell, 2013).