A gene long associated with autism, autism susceptibility candidate 2 (AUTS2), has been found to act through intermediaries to change the course of neurodevelopment. AUTS2 causes these intermediaries, members of the polycomb repressive complex 1 (PRC1), to switch from a gene-repression to a gene-activation program. By altering this program indirectly, AUTS2 acts as a master regulator gene, influencing epigenetic influencers that would otherwise maintain repressive forms of chromatin during crucial periods of developmental.

This finding, which points to a novel theory about how autism may develop as a consequence of disrupted brain pathways, emerged from studies conducted by researchers based at the NYU Langone Medical Center. The lead researcher, Danny Reinberg, Ph.D., said that his team’s work “offers strong supporting evidence that if autism spectrum disorders can be tied to widespread disruption of gene networks from multiple genetic lesions, then finding potential therapies could rest on research into repairing these gene network interruptions.”

The team presented their work December 17 in Nature, in an article entitled, “An AUTS2–Polycomb complex activates gene expression in the CNS.”

“Biochemical studies demonstrate that the CK2 component of PRC1–AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of P300 leads to gene activation,” wrote the article’s authors. “Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrated that AUTS2 regulates neuronal gene expression through promoter association.”

The researchers found that disrupting the function of AUTS2 in mice led to behaviors that were comparable to the neurologically delayed autistic behaviors observed in people. Additional experiments found that AUTS2 proteins were dominant in the cortex region of the mouse brain—the part of the brain involving memory, attention, and learning—and were more present in the first few weeks of life than after mice reach adulthood.

To further affirm their findings on the role of AUTS2 in controlling the syndrome, researchers genetically interrupted AUTS2 expression in mice and measured behavioral and motor-reflex effects. Mice with disrupted AUTS2 were slow to react, taking twice as long to right themselves after being placed on their backs, and making fewer than half as many calls after their mothers were taken away, than mice whose AUTS2 production was not impaired. Most AUTS2-deficient mice were also significantly shorter and had lower birth weights than mice producing AUTS2.

In discussing the significance of their work, the researchers ventured that their findings reflect how natural variation in the constituents of PRC1 complexes can lead to PRC1 adopting unexpected roles in coordinating specific cellular gene expression profiles: “Our findings may set a precedent for other dynamic alterations in the regulatory properties of PRC1 and perhaps PRC2, based on their constituent components.”

“The novel role of AUTS2 in modulating PRC1 activity to effectively remove its repressive function and exploit the complex to attain activated transcription,” concluded the authors of the Nature article, “will probably encourage alternate directions in addressing the challenges of ASD and related neurological diseases.”

Dr. Reinberg’s team plans further study of AUTS2 and its activities in other parts of the brain to uncover other possible links to ASDs or other neurological conditions, such as attention deficit hyperactivity disorder (ADHD) and schizophrenia.

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