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Autism Epigenetic Signature Detected Through Histone Acetylation-Wide Association Study

NEW YORK (GenomeWeb) – The tremendous clinical and genetic heterogeneity of autism spectrum disorder (ASD) may belie shared epigenetic underpinnings for many idiopathic and syndromic ASD cases, a new study suggests.

"Epigenome profiling has allowed us to see shared, unifying themes in what is often considered to be an amalgam of many different diseases rather than one single disease," co-senior author Daniel Geschwind, a neurogenetics researcher at the University of California at Los Angeles, said in a statement.

Geschwind and co-senior author Shyam Prabhakar from the Genome Institute of Singapore led a team of researchers from Singapore, the US, and the UK in performing a histone acetylation-wide association study, using information at H3K27ac marks in multiple post-mortem brain samples from dozens of individuals with or without ASD. The findings, published online today in Cell, suggest that histone acetylation patterns in two parts of the brain's cortex are similar across the majority of individuals with ASD.

"[D]espite tremendous heterogeneity in the primary causes of autism, such as DNA mutations and environmental perturbations during development, ASD has molecular features that are commonly shared," Prabhakar, a computational and systems biology researcher at GIS, said in a statement. "It is encouraging that ASD has common molecular changes, because this opens up the possibility of designing drugs to correct these changes."

The study is part of a package from investigators involved with the International Human Epigenome Consortium (IHEC). Dozens of studies, dealing with everything from neural conditions and development to cancer and immunity, were published in Cell, Cell Reports, Cell Metabolism, Cell Stem Cell, Cancer Cell, Cell Systems, Immunity, and other journals this week. Still more IHEC studies have been published over the course of the past year.

Recent ASD studies have started to untangle the vast collection of de novo structural variants, copy number changes, rearrangements, mitochondrial mutations, and other genetic alterations associated with the condition. There have also been clues that ASD may involve changes in the way genomic information is regulated. Such findings, coupled with the environmental contributors that have been described in ASD research, suggest that there may be characteristic epigenetic features in ASD.

With that in mind, Prabhakar, Geschwind, and their colleagues considered chromatin changes associated in 257 post-mortem brain samples — including samples from the prefrontal cortex, temporal cortex, and cerebellum brain regions — from 45 individuals with ASD and 49 unaffected control individuals. The ASD group included seven individuals with ASD cases attributed to a 15q duplication syndrome. The remaining ASD cases appeared to be idiopathic.

For its new analysis, the team did ChIP-seq with the Illumina HiSeq 2000, targeting H3K27ac — a histone acetylation mark that's been linked to active gene promoters and enhancers. The brain regions were selected because they fall in brain areas implicated in social cognition and/or animal studies of ASD.

From histone acetylation levels in the 81 prefrontal cortex, 66 temporal cortex, and 62 cerebellum samples left after their quality control steps, the researchers uncovered thousands of differentially acetylated loci in each of the cortex samples. Far fewer differentially acetylated sites turned up in the cerebellum samples.

The team refined its potential ASD acetylome signature by looking at how well differences in H3K27ac marks corresponded with expression shifts in the prefrontal cortex and temporal cortex, using data generated for the same individuals for a prior study.

After demonstrating that many of the same loci were differentially acetylated in ASD in the temporal and prefrontal cortexes, the researchers took a crack at teasing apart the possible functional consequences of such shifts. Many of the loci fell near known ASD-related genes and genes implicated in immune processes, ion transport, synaptic transmission, and neuronal activity, among other pathways.

With available RNA sequencing data from a human brain development atlas, meanwhile, they identified ASD-related changes in H3K27ac levels near genes synapse formation and neuronal maturation genes that are typically up-regulated during the first year of life.

By folding in information on transcription factor binding motifs and genotyping patterns for the individuals meanwhile, the researchers narrowed in on candidate transcription factors and quantitative trait loci, respectively, related to the histone signature in the cortexes. From more than 2,000 potential histone acetylation QTLs, for example, they uncovered two variants previously implicated in ASD or schizophrenia.

The study's authors cautioned that the histone acetylation signature described so far was not found in every ASD case, though it appeared that at least 80 percent of individuals with the condition had similar H3K27ac marks at more than 5,000 regulatory sites in the genome.

It remains to be seen whether the histone acetylation signature described in the study plays a causal role in ASD or whether the epigenetic shifts reflect other molecular changes behind the condition, the investigators noted.

It is also too soon to say whether the acetylation changes might be related to environmental factors that have been proposed in ASD, such as maternal infection or exposure to chemical toxins, Prabhakar told GenomeWeb in an email.

"The remarkable thing is that the acetylation aberrations in [individuals with the chromosome 7 duplication syndrome] were very similar to those we detected in the remaining 38 ASD cases," he explained. "This supports our conclusion that, although the primary causes of ASD are diverse, they nevertheless trigger similar downstream acetylation changes in individuals with ASD."

Members of the same team have been working on related studies focused on DNA methylation patterns associated with ASD, as well as analyses that bring together the available histone acetylation, DNA methylation, and other epigenetic information with gene expression data for individuals with ASD, Prabhakar noted.

The researchers are also interested in using mouse models to take a closer look at potential treatment targets have cropped up from their analyses so far. In parallel, he said, members of the team plan to use their general histone-wide association study strategy to examine other types of diseases, including autoimmune and metabolic conditions.

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