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.
Martinostat imaging of the human brain reveals levels of the epigenetic
enzymes called HDACs, with red reflecting the highest and blue the
lowest levels. Credit: H.-Y. Wey et al., Science Translational Medicine (2016))
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.”