title: Growth arrest and DNA-damage-inducible, beta (GADD45b)-mediated DNA demethylation in major psychosis.
abstract: Aberrant neocortical DNA methylation has been suggested to be a pathophysiological contributor to psychotic disorders. Recently, a growth arrest and DNA-damage-inducible, beta (GADD45b) protein-coordinated DNA demethylation pathway, utilizing cytidine deaminases and thymidine glycosylases, has been identified in the brain. We measured expression of several members of this pathway in parietal cortical samples from the Stanley Foundation Neuropathology Consortium (SFNC) cohort. We find an increase in GADD45b mRNA and protein in patients with psychosis. In immunohistochemistry experiments using samples from the Harvard Brain Tissue Resource Center, we report an increased number of GADD45b-stained cells in prefrontal cortical layers II, III, and V in psychotic patients. Brain-derived neurotrophic factor IX (BDNF IXabcd) was selected as a readout gene to determine the effects of GADD45b expression and promoter binding. We find that there is less GADD45b binding to the BDNF IXabcd promoter in psychotic subjects. Further, there is reduced BDNF IXabcd mRNA expression, and an increase in 5-methylcytosine and 5-hydroxymethylcytosine at its promoter. On the basis of these results, we conclude that GADD45b may be increased in psychosis compensatory to its inability to access gene promoter regions.
authors: Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago, Chicago, IL 60612, USA. dgavin@psych.uic.edu
authors: David P
authors: DP
authors: Gavin
authors: Rajiv P
authors: RP
authors: Sharma
authors: Kayla A
authors: KA
authors: Chase
authors: Francesco
authors: F
authors: Matrisciano
authors: Erbo
authors: E
authors: Dong
authors: Alessandro
authors: A
authors: Guidotti
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D000328:Adult; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016022:Case-Control Studies; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010296:Parietal Lobe / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011618:Psychotic Disorders / Q000235:genetics* / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D044503:5-Methylcytosine; D000943:Antigens, Differentiation; D019208:Brain-Derived Neurotrophic Factor; D003596:Cytosine; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C011865:5-hydroxymethylcytosine