title: Insights into neuroepigenetics through human histone deacetylase PET imaging.
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 [(11)C]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 [(11)C]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.
authors: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors: Hsiao-Ying
authors: HY
authors: Wey
authors: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors: Tonya M
authors: TM
authors: Gilbert
authors: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors: Nicole R
authors: NR
authors: Zürcher
authors: Chemical Neurobiology Laboratory, Departments of Neurology and Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Angela
authors: A
authors: She
authors: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors: Anisha
authors: A
authors: Bhanot
authors: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors: Brendan D
authors: BD
authors: Taillon
authors: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors: Fredrick A
authors: FA
authors: Schroeder
authors: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors: Changing
authors: C
authors: Wang
authors: Chemical Neurobiology Laboratory, Departments of Neurology and Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Stephen J
authors: SJ
authors: Haggarty
authors: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. hooker@nmr.mgh.harvard.edu.
authors: Jacob M
authors: JM
authors: Hooker
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000378:metabolism; D000328:Adult; D001921:Brain / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D005260:Female; D064368:Healthy Volunteers; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D000077153:Progranulins; D020033:Protein Isoforms / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D000077337:Vorinostat; D055815:Young Adult
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C492314:GRN protein, human; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D020033:Protein Isoforms; D016708:Synaptophysin; D000077337:Vorinostat; C000605558:martinostat; D006655:Histone Deacetylases; D000218:Adamantane