Epigenetic Signatures of Autism

Abstract

Prefrontal cortex neurons from subjects with autism show changes in chromatin structures at hundreds of loci genome-wide, revealing considerable overlap between genetic and epigenetic risk maps of developmental brain disorders.

Regulation of histone H3K4 methylation in brain development and disease

“…While there is no evidence to date that overall levels of H3K4 methylation are altered in brain tissue of subjects diagnosed with autism or schizophrenia [11,97], changes at specific loci have been reported. In a recent genome-wide study, H3K4me3 was quantified in neuronal chromatin from the prefrontal cortex of 16 subjects on the autism spectrum [11]. Remarkably, not a single locus reached statistical significance on the cohort level.…”

“…Furthermore, for many loci with an abnormal epigenetic signal in one (or several) autistic individuals, changes in gene expression could be documented for at least some of the very same cases with altered histone methylation. Based on these findings [11], one could conclude that each of the diseased brains showed a subject-specific H3K4 methylation signature, with each individual affected by a unique combinatorial set of abnormal histone methylation levels at select TSSs, together with altered expression of the associated gene transcripts. These individual-specific epigenetic alterations in the autism postmortem cohort included AUTS2, PARK2, RIA1, RIMS3, SHANK3, VGEL and many other susceptibility loci with high penetrance for disease risk.…”

“…Fifth, some drugs, including the atypical antipsychotic clozapine and the stimulant metamphetamine, alter H3K4 methylation signatures at specific gene promoters in cerebral cortex and striatum [12,96]. While there is no evidence to date that overall levels of H3K4 methylation are altered in brain tissue of subjects diagnosed with autism or schizophrenia [11,97], changes at specific loci have been reported. In a recent genome-wide study, H3K4me3 was quantified in neuronal chromatin from the prefrontal cortex of 16 subjects on the autism spectrum [11].…”

“…Whether the observed H3K4 methylation changes are linked to a DNA sequence alteration in cis or elsewhere in the genome (trans); reflect an adaptive or maladaptive response to environmental effects; are the outcome of some secondary or tertiary process in the neurobiology of disease; or are simply an epiphenomenon, remains to be determined in future studies. One interesting finding that emerged from the genome-wide, next-generation-sequencing-based mapping of H3K4me3 in prefrontal neurons of subjects with autism spectrum was the 'spreading' of this histone mark away from the TSSs and encroaching into gene bodies and upstream sequences [11] ( figure 2a,b). This alteration, which affected 4/16 cases but none of the controls, resulted in a significant broadening of the neuronal H3K4me3 peaks [11], which in normal brain are overwhelmingly organized into sharp peaks extending over 1-2 kb or less [4].…”

“…To date, mutations in five genes each encoding a H3K4-specific lysine methyltransferase or demethylase have been linked to developmental disability and impaired cognition, and several additional disease-associated genes encode proteins with a key regulatory role for H3K4 methylation [5]. Furthermore, there is evidence that H3K4 methylation landscapes in the human cerebral cortex are dynamically regulated during prenatal development and throughout early childhood years until adolescence [10], and potentially altered in some cases on the autism [11] or schizophrenia spectrum [12]. Therefore, the findings from clinical genetics and the conclusions drawn from the epigenome mappings in brain tissue coalesce, and when taken together, leave little doubt that fine-tuning of H3K4 methylation is of fundamental importance during an extended period of human brain development.…”