Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders.
BACKGROUND
To improve the understanding of psychotic abnormalities and their non-Mendelian inheritance patterns, the epigenetic regulation of the psychotic disorder-associated GABRB2, gene for the type A γ-aminobutyric acid receptor β(2)-subunit, was investigated.


METHODS
Expression of GABRB2, and the epigenetic regulatory enzymes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in mouse and postmortem human brains was analyzed using real-time PCR.


RESULTS
Results showed that expression of GABRB2 isoforms significantly increased over time in both mouse and human, especially for the long splicing isoform. In the brains of non-psychiatric controls (CON), a significant positive correlation of GABRB2 expression with age was observed in individuals with MM genotypes of the single nucleotide polymorphisms (SNPs) rs187269 and rs1816072. This was reversed to a significant negative correlation in schizophrenics (SCZ). A similar reversal was also displayed by bipolar disorder (BPD) patients. In parallel, a significant co-variation of HDAC1 with GABRB2 expression observed in CON remained significant in BPD but not in SCZ; comparably, a significant co-variation of HDAC2 with GABRB2 expression observed in CON became non-significant in both SCZ and BPD. Moreover, co-variations of DNMT1 and DNMT3B with GABRB2, not observable in CON, became significant in BPD.


CONCLUSIONS
These findings demonstrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. This study provided insight into the complex inheritance patterns of psychiatric disorders, and pointed to the involvement of epigenetic dysregulation in the disease process of major psychotic disorders.
Division of Life Science, Applied Genomics Center and Fok Ying Tung Graduate School, The Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.
Cunyou
C
Zhao
Feng
F
Wang
Frank W
FW
Pun
Lingling
L
Mei
Lihuan
L
Ren
Zhiliang
Z
Yu
Siu-Kin
SK
Ng
Jianhuan
J
Chen
Shui-Ying
SY
Tsang
Hong
H
Xue
D000328:Adult; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001714:Bipolar Disorder / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D015254:DNA Modification Methylases / Q000378:metabolism; D004622:Embryo, Mammalian; D057890:Epigenomics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011180:Postmortem Changes; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D013223:Statistics as Topic
C495710:GABRB2 protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D015254:DNA Modification Methylases; D006655:Histone Deacetylases