Research ArticleBrain Imaging

Insights into neuroepigenetics through human histone deacetylase PET imaging

Science Translational Medicine  10 Aug 2016:
Vol. 8, Issue 351, pp. 351ra106
DOI: 10.1126/scitranslmed.aaf7551

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Brain epigenetics revealed

Certain enzymes called histone deacetylases, or HDACs, are part of the epigenetic machinery that regulates gene transcription. In neurological disorders, HDACs change expression in regions throughout the brain, but their dynamic contribution to human disease development over time is unknown. Wey et al. therefore developed and applied an HDAC imaging probe, called Martinostat, to visualize HDAC expression in the living brain. Martinostat was previously tested in rodents and nonhuman primates, and here, it is used for the first time in humans. The authors saw surprisingly conserved regions of HDAC expression in the healthy brain, suggesting tightly regulated epigenetic processes. In human stem cell–derived neural progenitor cells, Martinostat engaged the subset HDACs that regulate downstream genes important for neuroplasticity, memory, and neurodegeneration, supporting its use in monitoring and understanding brain pathologies like Alzheimer’s disease.

Abstract

Epigenetic dysfunction is implicated in many neurological and psychiatric diseases, including Alzheimer’s disease and schizophrenia. Consequently, histone deacetylases (HDACs) are being aggressively pursued as therapeutic targets. However, a fundamental knowledge gap exists regarding the expression and distribution of HDACs in healthy individuals for comparison to disease states. Here, we report the first-in-human evaluation of neuroepigenetic regulation in vivo. Using positron emission tomography with [11C]Martinostat, an imaging probe selective for class I HDACs (isoforms 1, 2, and 3), we found that HDAC expression is higher in cortical gray matter than in white matter, with conserved regional distribution patterns within and between healthy individuals. Among gray matter regions, HDAC expression was lowest in the hippocampus and amygdala. Through biochemical profiling of postmortem human brain tissue, we confirmed that [11C]Martinostat selectively binds HDAC isoforms 1, 2, and 3, the HDAC subtypes most implicated in regulating neuroplasticity and cognitive function. In human stem cell–derived neural progenitor cells, pharmacologic-level doses of Martinostat induced changes in genes closely associated with synaptic plasticity, including BDNF (brain-derived neurotrophic factor) and SYP (synaptophysin), as well as genes implicated in neurodegeneration, including GRN (progranulin), at the transcript level, in concert with increased acetylation at both histone H3 lysine 9 and histone H4 lysine 12. This study quantifies HDAC expression in the living human brain and provides the foundation for gaining unprecedented in vivo epigenetic information in health and disease.

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