title: Mining the topography and dynamics of the 4D Nucleome to identify novel CNS drug pathways.
abstract: The pharmacoepigenome can be defined as the active, noncoding province of the genome including canonical spatial and temporal regulatory mechanisms of gene regulation that respond to xenobiotic stimuli. Many psychotropic drugs that have been in clinical use for decades have ill-defined mechanisms of action that are beginning to be resolved as we understand the transcriptional hierarchy and dynamics of the nucleus. In this review, we describe spatial, temporal and biomechanical mechanisms mediated by psychotropic medications. Focus is placed on a bioinformatics pipeline that can be used both for detection of pharmacoepigenomic variants that discretize drug response and adverse events to improve pharmacogenomic testing, and for the discovery of novel CNS therapeutics. This approach integrates the functional topology and dynamics of the transcriptional hierarchy of the pharmacoepigenome, gene variant-driven identification of pharmacogenomic regulatory domains, and mesoscale mapping for the discovery of novel CNS pharmacodynamic pathways in human brain. Examples of the application of this pipeline are provided, including the discovery of valproic acid (VPA) mediated transcriptional reprogramming of neuronal cell fate following injury, and mapping of a CNS pathway glutamatergic pathway for the mood stabilizer lithium. These examples in regulatory pharmacoepigenomics illustrate how ongoing research using the 4D nucleome provides a foundation to further insight into previously unrecognized psychotropic drug pharmacodynamic pathways in the human CNS.
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, USA.
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Higgins
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Allyn-Feuer
authors.affiliation: Department of Surgery, University of Michigan Medical School, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Georgoff
authors.affiliation: Department of Surgery, University of Michigan Medical School, USA.
authors.forename: Vahagn
authors.initials: V
authors.lastname: Nikolian
authors.affiliation: Department of Surgery, University of Michigan Medical School, USA.
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, USA; Michigan Institute for Data Science (MIDAS), USA. Electronic address: bleu@med.umich.edu.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Athey
mesh_terms: D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002877:Chromosomes, Human / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002940:Circadian Rhythm / Q000502:physiology; D019295:Computational Biology / Q000379:methods*; D057225:Data Mining / Q000379:methods; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D008094:Lithium / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010597:Pharmacogenetics / Q000379:methods*; D011619:Psychotropic Drugs / Q000627:therapeutic use*; D014158:Transcription, Genetic; D014635:Valproic Acid / Q000627:therapeutic use
chemical_list: D009419:Nerve Tissue Proteins; D011619:Psychotropic Drugs; D014635:Valproic Acid; D008094:Lithium
keywords: Circadian rhythmicity; Gene regulation; Mechanogenomics; Non-coding genome; Pharmacoepigenomics; Transcription