title: Stress and glucocorticoid receptor transcriptional programming in time and space: Implications for the brain-gut axis.
abstract: BACKGROUND
  Chronic psychological stress is associated with enhanced abdominal pain and altered intestinal barrier function that may result from a perturbation in the hypothalamic-pituitary-adrenal (HPA) axis. The glucocorticoid receptor (GR) exploits diverse mechanisms to activate or suppress congeneric gene expression, with regulatory variation associated with stress-related disorders in psychiatry and gastroenterology.
  
  
  OBJECTIVE
  During acute and chronic stress, corticotropin-releasing hormone drives secretion of adrenocorticotropic hormone from the pituitary, ultimately leading to the release of cortisol (human) and corticosterone (rodent) from the adrenal glands. Cortisol binds with the GR in the cytosol, translocates to the nucleus, and activates the NR3C1 (nuclear receptor subfamily 3, group C, member 1 [GR]) gene. This review focuses on the rapidly developing observations that cortisol is responsible for driving circadian and ultradian bursts of transcriptional activity in the CLOCK (clock circadian regulator) and PER (period circadian clock 1) gene families, and this rhythm is disrupted in major depressive disorder, bipolar disorder, and stress-related gastrointestinal and immune disorders. Glucocorticoid receptor regulates different sets of transcripts in a tissue-specific manner, through pulsatile waves of gene expression that includes occupancy of glucocorticoid response elements located within constitutively open spatial domains in chromatin. Emerging evidence supports a potentially pivotal role for epigenetic regulation of how GR interacts with other chromatin regulators to control the expression of its target genes. Dysregulation of the central and peripheral GR regulome has potentially significant consequences for stress-related disorders affecting the brain-gut axis.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Wiley
authors.affiliation: Department of Pharmacogenomic Science, Assurex Health, Inc., Mason, OH, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Higgins
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Athey
mesh_terms: D015746:Abdominal Pain / Q000235:genetics* / Q000378:metabolism; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D056926:CLOCK Proteins / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003865:Major Depressive Disorder / Q000235:genetics / Q000378:metabolism; D005767:Gastrointestinal Diseases / Q000235:genetics / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D006930:Hyperalgesia / Q000235:genetics* / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D056950:Period Circadian Proteins / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C497713:NR3C1 protein, human; D056950:Period Circadian Proteins; D011965:Receptors, Glucocorticoid; D003346:Corticotropin-Releasing Hormone; D056926:CLOCK Proteins; D006854:Hydrocortisone
keywords: CLOCK genes; chronic stress; epigenomics; intestinal barrier function; irritable bowel syndrome; mental health disorders