Autism is a heterogeneous brain disorder believed to have both genetic and environmental contributions. Epigenetic mechanisms, including modification of DNA and histones — proteins that store and organize DNA — allow an organism to respond to the environment through changes in gene expression. There is compelling evidence from human genetic association studies and animal models supporting a role for epigenetic dysregulation in autism. In particular, defects in MeCP2 protein function cause Rett syndrome. In this pilot study, Hongjun Song and his colleagues at Johns Hopkins University School of Medicine in Baltimore explored the role of DNA modifications in neuronal gene expression, plasticity, behavior and autism.

In the human genome, there are four bases: cytosine (C), thymine (T), adenine (A) and guanine (G). It is often believed that C can have a chemical modification called methylation that only occurs when G follows C in the genome (CpG). Song and his group discovered that, in contrast to this common belief, modification of DNA in the non-CG context — for example, C followed by A (CpA) — is prominent in neurons and is established during neuronal maturation¹.

They further identified MeCP2 as a reader, and DNMT3A as a writer, for non-CpG methylation in neurons. These characteristics of non-CpG methylation suggest that a substantially expanded proportion of the neuronal genome is under DNA methylation regulation and provide a new foundation for understanding the role of this key epigenetic modification in the nervous system. Recent studies overturned the previous understanding that DNA methylation is largely fixed and irreversible in fully differentiated cells², ³. Instead, the neuronal methylome is highly dynamic in response to neuronal activity, including active addition and removal of DNA demethylation².

The researchers also identified molecular machinery that mediates active DNA demethylation in neurons, involving GADD45B and the DNA repair pathway³. They found that GADD45B is aberrantly expressed in postmortem brain samples from individuals with autism compared with controls. They showed that neuronal activity regulates GADD45B expression, which in turn regulates neuronal activity, induced gene expression and synaptic plasticity — the ability of neurons to change the strength of their connections. In addition, mice that lack GADD45B exhibit deficits in behavioral tests for autism. The group’s findings open new avenues to understand the mechanisms underlying autism.