First imaging of brain epigenetics achieved with new PET radiochemical

Harvard researchers have developed a novel PET radiotracer that can reveal genetic expression, or lack thereof, in the brain enzymes called histone deacetylases (HDACs).

As these enzymes are key components in the regulation of gene transcription—in which a specific protein forms upon the copying of genetic information from DNA to RNA—the work sets the stage for the gaining of “unprecedented in vivo epigenetic information in health and disease,” the researchers write in a report published online Aug. 10 in Science Translational Medicine.

In introducing their work, Hsiao-Ying (Monica) Wey, PhD, and colleagues at Massachusetts General Hospital’s Martinos Center for Biomedical Imaging note that epigenetic dysfunction is associated with Alzheimer’s disease, schizophrenia and other neurological and psychiatric diseases.

HDACs have previously been singled out as prime therapeutic targets, but not much has been known about how the enzyme’s expression and distribution differ between healthy and diseased brains.

The team says its first-in-human research, which was made possible by the participation of eight healthy volunteers, also represents the first evaluation of neuroepigenetic regulation in vivo.

Using PET with their novel tracer—which they’re calling Martinostat—they found that HDAC expression is “higher in cortical gray matter than in white matter, with conserved regional distribution patterns within and between healthy individuals,” the authors write. “Among gray matter regions, HDAC expression was lowest in the hippocampus and amygdala.”

Subsequently, by biochemically profiling postmortem human brain tissue, the researchers confirmed that Martinostat selectively binds HDAC isoforms that are understood to be most responsible for regulating neuroplasticity and cognitive function.

In a news release from Mass General, the study’s senior author, Jacob Hooker, PhD, says the ability to image “the epigenetic machinery in the human brain” may show how genes interact with the environment and other variables.  

“This could allow us to investigate questions such as why some people genetically predisposed to a disease are protected from it,” adds Hooker. “Why [do] 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?”

The journal has posted the full study for free.