Growth arrest and DNA-damage-inducible, beta (GADD45b)-mediated DNA demethylation in major psychosis

David P. Gavin*, Rajiv P. Sharma, Kayla A. Chase, Francesco Matrisciano, Erbo Dong, Alessandro Guidotti

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)531-542
Number of pages12
JournalNeuropsychopharmacology
Volume37
Issue number2
DOIs
StatePublished - Jan 2012

Keywords

  • CpG
  • DNA methylation
  • bipolar disorder
  • epigenetic
  • histone
  • schizophrenia

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Fingerprint Dive into the research topics of 'Growth arrest and DNA-damage-inducible, beta (GADD45b)-mediated DNA demethylation in major psychosis'. Together they form a unique fingerprint.

Cite this