Mouse Study Verifies Gene’s Role in Autism Via Epigenetics

Child Playing With Puzzle Pieces Epigenetics

More families are living with autism today than ever before. It’s a common diagnosis with a prevalence of 1 in 59 children in the US. Despite all the efforts to understand this condition, there is still no known cause.

The consensus among researchers is that autism is predominantly genetic with a few environmental factors involved. However, determining a heritable link here is complex since any number of genotypic variations could underlie autism. To better pinpoint genes that may contribute to the etiology of autism, scientists have expanded their research to include epigenetics.

One particular gene involved in neurodevelopment and associated behaviors is SETD5. As a member of the SET domain family of histone methyltransferase (HMTs), this gene has been found in other studies to influence early development, thus making it a top candidate gene for autism spectrum disorder (ASD).

In a recent study, scientists may have confirmed SETD5’s role in ASD using a novel mouse model. They have reported that this gene epigenetically drives aberrant neurodevelopment leading to behavioral deficits typically found in ASD. Their findings are available in the January issue of Translational Psychiatry.

“We only had clinical and genetic evidence that the gene was related to autism,” said lead author, Alysson R. Muotri, Ph.D. “Now, with this mouse model, we have direct causal evidence linking this gene with neuronal molecular and cellular alterations leading to ASD-like behavior.”

Establishing valid animal models for ASD has always been challenging given symptoms of this disorder are heterogeneous among patients. The researchers believe that this mouse model could be useful for testing potential therapies for this subclass of ASD.

Because ASD is a multigenic condition, it has been thought to be dependent on epigenetics. Epigenetics refers to changes in gene expression that do not alter to the underlying DNA code. It also has been used to describe heritable changes in phenotype resulting from environmental factors. Mechanisms altering gene expression include DNA methylation and histone modifications.

Chromatin remodeling, or how DNA is packed inside the nucleus of a cell, is highly implicated in epigenetics. The arrangement of chromatin (either open or closed) determines gene expression, which in turn controls many cellular processes including cell division and neural development. In previous articles, we’ve reported on how chromatin structure was the main factor in suppressing genes linked to autism and fragile X syndrome, a genetic mental impairment disorder.

Muotri pointed out, “The importance of epigenetic regulatory mechanisms is increasingly appreciated in human neurodevelopment and neurodevelopmental conditions, such as ASD. Indeed, mutations in chromatin-related epigenetic genes can cause several neurological disorders.”

The researchers took advantage of utilizing a mouse model with SETD5 haploinsufficiency, or one working copy of the gene. They found morphological alterations in the cortical nerve cells of the SETD5 model with reduced connectivity. “As a consequence, the neuronal networks showed a delayed in development in these mice compared to controls,” said Muotri.

The team then located the neurodevelopmental downregulated genes affected by SETD5. They assumed that the altered gene expression would result in abnormal behavior and, as expected, the modified mice portrayed autistic-like social conduct.  An MRI also revealed slight anatomical changes in the adult brains of these mice. As well, a more in-depth investigation showed aberrant cortical lamination, a factor evident in other ASD models. 

While more research is needed, the overall findings from this study suggest a role for SETD5 in the pathogenesis of certain subpopulations of ASD. The new animal model will also allow researchers to improve upon our understanding of ASD and hopefully develop therapies that alleviate the negative symptoms of this disorder.

Source: Moore, S. M. et al. (2019) Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice. Translational Psychiatry.

Reference: University of California – San Diego. “Novel autism mouse model based on an epigenetic gene developed” January 2019.

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