Autism can arise from mutations that disrupt the activity of some genes, but the mutations discovered so far explain only a modest fraction of autism cases. Arthur Beaudet and his colleagues at Baylor College of Medicine are instead focusing on the epigenetic systems that control whether a gene is turned on or off through the regulation of genome structure.
In the nucleus, DNA wraps around proteins to form a structure known as chromatin, and epigenetic modifications to either the proteins or the DNA can determine whether the chromatin hides or exposes a gene for RNA production. These modifications can include methylation of DNA at cytosine bases in the gene regulatory regions or adding methyl-, phosphate- or acetyl-groups to the wrapped histone proteins. Chromatin modifications can have a wide-ranging impact on which genes are expressed, even without a mutation in the DNA sequence.
Beaudet and his colleagues are looking for unusual patterns of chromatin modifications associated with autism, using techniques that uncover these marks on the proteins and DNA recovered from the nuclei of neurons. From the postmortem brain tissue from people with autism, the team plans to isolate chromatin and use antibodies to detect particular histone modifications known to affect gene expression. The researchers will also sequence the isolated DNA, looking for both mutations and methylation marks; they have already used these techniques to detect known epigenetic abnormalities associated with Prader-Willi and Angelman syndromes, developmental disorders that present with learning disabilities and some autism-like symptoms.
This combined strategy allows unbiased screening of the chromatin in the neuron nuclei across the entire genome but the researchers will also meticulously analyze autism-associated genomic regions with even higher resolution to detect any epigenetic changes that would not be detected by traditional sequencing. In a complementary set of experiments, the investigators are carefully assaying the neurons' RNA profiles to determine which genes are up- or down-regulated in autism, which may point to new genes or pathways.
Epigenetic modifications can vary between tissues, so the researchers are starting with brain samples. But if the marks they discover are also found in other tissues, such as blood or skin, a simpler screen could perhaps be developed for earlier and more accurate diagnoses of autism.