CHICAGO – Evidence and understanding is mounting of the central role that epigenetic alterations of gene expression play in brain disorders ranging from schizophrenia to post-traumatic stress and Huntington’s disease, pointing the way to a swathe of potential new therapeutic targets.

“Epigenetic changes can occur in the brain and persistently alter gene expression and affect disease, behavior and memory, and are implicated in substance abuse,” said Joseph Coyle, professor of psychiatry and neuroscience at Harvard Medical School. “What’s particularly exciting and important is that these changes may be responsive to pharmacology, so what is seen as irreversible can be modulated.”

One of the key pieces of research that is opening up the possibility of using epigenetic modification to treat brain disorders involves the elucidation of epigenetic mechanisms that underlie learning and memory.

“When you make a memory in your brain it requires a chemical modification of DNA for memory formation and storage. We are now trying to understand these modalities so we can make new and better drugs for Alzheimer’s disease and other disorders,” said David Sweatt, professor of neurobiology at the University of Alabama, a pioneer in showing that learning and memory involves epigenetic regulation.

Sweatt’s current work is looking at the effect of chemical modification in reward-mediated behavior. “We have discovered that when an animal gets a rewarding experience and modulates behavior there are changes in DNA methylation,” Sweatt said. If the methylation changes are reversed or blocked it is no longer possible to change behavior. “In other words, changes in DNA methylation can change behavior forever,” Sweatt noted. “Changes are long-lasting and mediate life-long changes.”

As yet the precise epigenetic changes that occur when a long-term memory is laid down are not known. However, Sweatt said new tools for manipulating the epigenome that are now in striking distance, promise to fill this gap in understanding.

Schahram Akbarian, professor of neuroscience at Mount Sinai Medical School in New York, said he is “not a neo-Lamarckian,” but the evidence now demonstrates that chemical modification of DNA through the epigenome “is active from the second of conception and plays an important role across the entire life span.”

These modifications are central in the development of the brain. “They are important in medicine for a wide range of disorders from cancer to autism, depression and schizophrenia,” Akbarian said.

One epigenetics project that is in sight of the clinic involves repurposing histone deacetylase inhibitors used in treating cancer for the treatment of Huntington’s disease. One of the hallmarks of the pathophysiology of this inherited disorder is that transcription goes awry, and Ghazaleh Sadri-Vakili, assistant professor of neurology at Massachusetts General Hospital, of Boston, has shown that alteration of histone acetylation is one mechanism that underlies this transcriptional dysregulation in Huntington’s disease. “HDACs used in cancer are effective in fly [drosophila] and mouse models,” she said.

A screen of 70 compounds has thrown up six hits, and work is progressing to develop a new scaffold to decrease toxicity and side effects. “We hope within the next two years to put forward a candidate for clinical testing,” Sadri-Vakili said.

Similarly, Sweatt noted there is a substantial body of evidence implicating epigenetic modifications in autism spectrum disorders, including Rett’s syndrome and Asperger’s disorder. “This is a good area for research and may be fertile for finding new treatments for autism spectrum disorders and intellectual impairment,” he said.

Histones and other epigenome modulators are widespread in the body, raising concerns about unwanted side effects, especially if inhibitors are to be used for long-term treatments. However, Sweatt said this is “potentially positive” in treating brain disorders in which many genes are involved.

“To treat brain disease you need a multi-targeted drug that can affect a lot of genes epigenetically,” Sweatt added.