New PET scan tracer allows first imaging of the epigenetics of the human brain
A novel PET radiotracer developed at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital (MGH) is able for the first time to reveal epigenetic activity – the process that determines whether or not genes are expressed – within the human brain. In their report published in Science Translational Medicine, a team of MGH/Martinos Center investigators reports 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, PhD, 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?"
A key epigenetic mechanism is the packaging of DNA into chromosomes, in which it wraps around proteins called histones forming a structure called chromatin. Modification of histones by the addition or removal of molecules called epigenetic factors can regulate whether or not an adjacent gene is expressed. One of the most important of these factors is the acetyl molecule, addition of which allows a gene to be transcribed and removal of which – called deacetylation – prevents transcription.
Enzymes called 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 Hooker's laboratory and is patterned after known HDAC inhibitors in order to tightly bind to HDAC molecules 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; and 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 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."
The co-lead authors of the Science Translational Medicine paper are Hsiao-Ying Wey, PhD, and Tonya Gilbert, PhD, of the Martinos Center. Additional co-authors are Nicole Zürcher, PhD, Anisha Bhanot, Brendan Taillon, Fredrick Schroeder and Changning Wang, PhD, Martinos Center; and Angela She and Stephen J. Haggarty, PhD, Chemical Neurobiology Laboratory, MGH Departments of Neurology and Psychiatry. The study was primarily funded by National Institutes of Health grants R01 DA030321 and K99 DA037928. A patent application covering Martinostat has been filed in several territories and limited commercial rights have been licensed.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute) conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals, earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."