Epigenetic activity within the human brain has been imaged for the first time, with the help of a novel positron emission tomography radiotracer developed at Massachusetts General Hospital. The radiochemical, named Martinostat, showed the expression levels of important epigenetics-regulating enzymes in the brains of healthy volunteers.

Epigenetics is the process that determines whether or not genes are expressed. Jacob Hooker, PhD, of the Martinos Center for Biomedical Imaging, senior author of the report, explains:

“The ability to image the epigenetic machinery in the human brain can provide a way to begin understanding interactions between genes and the environment. 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 Deacetylase

One 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.

[caption id=“attachment_84143” align=“aligncenter” width=“680”]Kinetic modeling results Kinetic modeling results with [11C]6 in baboon brain. Credit: Changning Wang, et al. DOI: 10.1021/jm500872p[/caption]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.

Understanding Brain Diseases

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.

H.-Y. Wey, T. M. Gilbert, N. R. Zurcher, A. She, A. Bhanot, B. D. Taillon, F. A. Schroeder, C. Wang, S. J. Haggarty, J. M. Hooker Insights into neuroepigenetics through human histone deacetylase PET imaging Science Translational Medicine, 2016; 8 (351): 351ra106 DOI: 10.1126/scitranslmed.aaf7551

Top Image: a translational PET imaging probe, using Martinostat. Credit: Changning Wang, et al. DOI: 10.1021/jm500872p CC BY

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