Changes in epigenetic marks (H3K27) in three brain regions from patients with ASD-revealed shared molecular and cellular pathways. Graphic: Courtesy of Drs. Daniel Geschwind and Shyam Prabhakar
UCLA scientists and their colleagues have found evidence that an abnormal pattern of brain cells is common in people with different types of autism-spectrum disorders. The abnormal pattern discovered in the study concerns a certain type of “epigenetic mark,” a chemical modification that occurs frequently on chromosomes and helps regulate the activity of nearby genes.
The findings suggest that although autism-spectrum disorders have multiple causes, they mostly involve problems in a common set of biological pathways, which are actions among certain molecules within a cell that lead to specific changes such as turning genes on or off or assembling new molecules. The findings may lead to a better understanding of how autism-spectrum disorders arise and perhaps one day to the development of drugs that target some of these irregular pathways.
“The uniformity of this abnormal pattern in the autism samples was surprising, given that these samples were from people whose autism was known to have different causes,” says Daniel Geschwind, MD (RES ’95, FEL ’97), PhD, Gordon and Virginia MacDonald Distinguished Chair in Human Genetics. “It suggests the possibility that different factors can cause autism-spectrum disorders through a set of common pathways.”
Dr. Geschwind and his colleagues, including Shyam Prabhakar, PhD, of the Genome Institute of Singapore, evaluated brain tissue of 45 people who had autism-spectrum disorders and 49 who did not. The team mapped one specific type of epigenetic mark called “histone acetylation.” Epigenetic abnormalities are certainly plausible suspects in autism disorders, says Dr. Geschwind, who also is professor of neurology and psychiatry and biobehavioral sciences. They are not only extremely common — occurring in about one-in-68 American children — but also have no known cause in most cases.
In the study, the mapping of histone acetylation marks revealed the same broad pattern or “signature” of abnormality in more than 80 percent of the samples from the cerebral cortexes of the autism cases compared to the non-autism cases. The cortex, the most advanced brain region, is the one that appears to be most affected in autism-spectrum disorders. The abnormal pattern, which did not appear in samples from other parts of the brain, involved changes at more than 5,000 locations on the human genome. These changes mirrored findings from the team’s earlier studies. Connecting these different levels of analysis is one of the next challenges facing the researchers.
Scientists have only recently begun to conduct systematic investigations of epigenetic abnormalities in people, but they have already found that these abnormal chemical modifications contribute to cancers and other diseases. This study was the first to map this type of epigenetic mark across the genome in a human brain disease.
The team now hopes to determine which of the many epigenetic abnormalities uncovered in the study are true causes of autism behaviors — and therefore could be potential targets for future autism drugs. Drugs that affect histone acetylation have already been developed as potential cancer treatments, and some older psychiatric drugs also influence histone acetylation; however, knowing which changes are the key to target still represents a formidable challenge.
“Histone Acetylome-wide Association Study of Autism Spectrum Disorder,” Cell, November 17, 2016