Single immobilization stress differentially alters the expression profile of transcripts of the brain-derived neurotrophic factor (BDNF) gene and histone acetylation at its promoters in the rat hippocampus.
Decreased levels of brain-derived neurotrophic factor (BDNF) in the hippocampus are implicated in the pathophysiology of major depression, although the mechanism has yet to be characterized. Epigenetic studies revealed that DNA methylation and histone modifications at the promoter of exons of the BDNF gene are the pivotal factors in the regulation of BDNF transcription. Histone acetylation regulates gene transcription through chromatin remodelling. We examined the influence of a single immobilization stress (SIS) at 2 h and 24 h afterwards on the levels of total BDNF mRNA with each exon mRNA by quantitative real-time PCR, acetylated histone at the promoters of the BDNF gene by chromatin immunoprecipitation followed by real-time PCR, and BDNF protein by ELISA in the rat hippocampus. SIS significantly decreased the levels of total BDNF mRNA with significantly reduced levels of exons I and IV mRNA followed by a significant reduction in BDNF protein 4 h after SIS. Significant decreases in the levels of acetylated histone H3, but not H4, were found at the promoters of exons I, IV, and VI. In contrast, no marked changes in the levels of either acetylated histone or BDNF mRNA and protein were found 24 h after SIS. This study demonstrated the involvement of histone acetylation in the regulation of BDNF transcription by SIS, and the plastic change in histone acetylation after SIS. These findings suggest that stress affects BDNF gene transcription via epigenetic regulation, and glucocorticoid may be involved in this regulation.
Department of Psychiatry and Neurosciences, Division of Frontier Medicine, Graduate School of Medical Sciences, Hiroshima University, Hiroshima, Japan.
Manabu
M
Fuchikami
Shigeru
S
Morinobu
Akiko
A
Kurata
Shigeto
S
Yamamoto
Shigeto
S
Yamawaki
D000107:Acetylation; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D003345:Corticosterone / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005091:Exons / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013315:Stress, Psychological / Q000378:metabolism / Q000523:psychology*; D020506:Untranslated Regions / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; D020506:Untranslated Regions; D003345:Corticosterone