Elevated transcription factor specificity protein 1 in autistic brains alters the expression of autism candidate genes.
BACKGROUND
Profound changes in gene expression can result from abnormalities in the concentrations of sequence-specific transcription factors like specificity protein 1 (Sp1). Specificity protein 1 binding sites have been reported in the promoter regions of several genes implicated in autism. We hypothesize that dysfunction of Sp1 could affect the expression of multiple autism candidate genes, contributing to the heterogeneity of autism.


METHODS
We assessed any alterations in the expression of Sp1 and that of autism candidate genes in the postmortem brain (anterior cingulate gyrus [ACG], motor cortex, and thalamus) of autism patients (n = 8) compared with healthy control subjects (n = 13). Alterations in the expression of candidate genes upon Sp1/DNA binding inhibition with mithramycin and Sp1 silencing by RNAi were studied in SK-N-SH neuronal cells.


RESULTS
We observed elevated expression of Sp1 in ACG of autism patients (p = .010). We also observed altered expression of several autism candidate genes. GABRB3, RELN, and HTR2A showed reduced expression, whereas CD38, ITGB3, MAOA, MECP2, OXTR, and PTEN showed elevated expression in autism. In SK-N-SH cells, OXTR, PTEN, and RELN showed reduced expression upon Sp1/DNA binding inhibition and Sp1 silencing. The RNA integrity number was not available for any of the samples.


CONCLUSIONS
Transcription factor Sp1 is dysfunctional in the ACG of autistic brain. Consequently, the expression of potential autism candidate genes regulated by Sp1, especially OXTR and PTEN, could be affected. The diverse downstream pathways mediated by the Sp1-regulated genes, along with the environmental and intracellular signal-related regulation of Sp1, could explain the complex phenotypes associated with autism.
Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Japan.
Ismail
I
Thanseem
Ayyappan
A
Anitha
Kazuhiko
K
Nakamura
Shiro
S
Suda
Keiko
K
Iwata
Hideo
H
Matsuzaki
Masafumi
M
Ohtsubo
Takatoshi
T
Ueki
Taiichi
T
Katayama
Yasuhide
Y
Iwata
Katsuaki
K
Suzuki
Shinsei
S
Minoshima
Norio
N
Mori
D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D008297:Male; D008926:Plicamycin / Q000494:pharmacology; D034622:RNA Interference; D000091042:Reelin Protein; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D000091042:Reelin Protein; D016329:Sp1 Transcription Factor; C000717127:RELN protein, human; D008926:Plicamycin