Scientists at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital (MGH) say they have developed a novel positron emission tomography (PET) radiotracer that reveals epigenetic activity within the human brain. In their report (“Insights into Neuroepigenetics through Human Histone Deacetylase PET Imaging”), published in Science Translational Medicine, the investigators report how their radiochemical, called Martinostat, shows the expression levels of important epigenetics-regulating enzymes in the brains of healthy volunteers.
“The ability to image the epigenetic machinery in the human brain can provide a way to begin understanding interactions between genes and the environment,” says Jacob Hooker, Ph.D., of the Martinos Center, senior author of the report. “This could allow us to investigate questions such as why some people genetically predisposed to a disease are protected from it? Why events during early life and adolescence have such a lasting impact on brain health? Is it possible to 'reset' gene expression in the human brain?”
Histone deacetylases (HDAC) are important regulators of gene transcription, and one group of HDACs has been linked to important brain disorders. Several established neuropsychiatric drugs are HDAC inhibitors, and others are currently being studied as potential treatment for Alzheimer's disease and Huntington's disease. Martinostat was developed in Dr. Hooker's laboratory and is patterned after known HDAC inhibitors to bind to HDAC molecules tightly in the brain.
PET scans with Martinostat of the brains of eight healthy human volunteers revealed characteristic patterns of uptake, reflecting HDAC expression levels, that were consistent among all participants. HDAC expression was almost twice as high in gray matter as in white matter. Within gray matter structures, uptake was highest in the hippocampus and amygdala and lowest in the putamen and cerebellum. Experiments with brain tissues from humans and baboons confirmed Martinostat's binding to HDAC, and studies with neural progenitor stem cells revealed specific genes regulated by this group of HDACs, many of which are known to be important in brain health and disease.
“HDAC dysregulation has been implicated in a growing number of brain diseases, so being able to study HDAC regulation both in the normal brain and through the progression of disease should help us better understand disease processes,” says Dr. Hooker, who is an associate professor of radiology at Harvard Medical School. “We've now started studies of patients with several neurologic or psychiatric disorders, and I believe Martinostat will help us understand the different ways these conditions are manifested and provide new insights into potential therapies.”