This review identifies mechanisms for altering DNA-histone interactions of cell chromatin to upregulate or downregulate gene expression that could serve as epigenetic targets for therapeutic interventions in autism. DNA methyltransferases (DNMTs) can phosphorylate histone H3 at T6. Aided by protein kinase Cβ1, the DNMT lysine-specific demethylase-1 prevents demethylation of H3 at K4. During androgen-receptor-(AR-) dependent gene activation, this sequence may produce AR-dependent gene overactivation which may partly explain the male predominance of autism. AR-dependent gene overactivation in conjunction with a DNMT mechanism for methylating oxytocin receptors could produce high arousal inputs to the amygdala resulting in aberrant socialization, a prime characteristic of autism. Dysregulation of histone methyltransferases and histone deacetylases (HDACs) associated with low activity of methyl CpG binding protein-2 at cytosine-guanine sites in genes may reduce the capacity for condensing chromatin and silencing genes in frontal cortex, a site characterized by decreased cortical interconnectivity in autistic subjects. HDAC1 inhibition can overactivate mRNA transcription, a putative mechanism for the increased number of cerebral cortical columns and local frontal cortex hyperactivity in autistic individuals. These epigenetic mechanisms underlying male predominance, aberrant social interaction, and low functioning frontal cortex may be novel targets for autism prevention and treatment strategies. 1. Introduction Autism spectrum disorders (ASDs) are a range of neurodevelopmental disorders typically characterized by repetitive and stereotyped behavior, limited social development, and impaired language skills. Autistic disorder, Asperger syndrome, and pervasive development disorder not otherwise specified (PDD-NOS) are the most commonly diagnosed ASDs and there are also a large number of cases that are considered idiopathic because the etiology is unclear [1]. Notably, the incidence of ASD diagnoses has increased substantially in the past twenty years, growing by as much as 5- or 10-fold, although, the approximate 4？:？1 ratio of affected males to female has been maintained [2]. Some of this increase has been driven by shifting diagnostic criteria, heightened awareness, and improved diagnostic techniques [3]. However, some of this increase could be attributable to an authentic increase in the frequency of ASDs. The identity of the factors fueling this increase remains somewhat elusive and the precise causes of ASD diagnoses remain unknown [4]. Although its basis
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