Abstract
Reduction of Sp4 expression causes age-dependent hippocampal vacuolization and many other intermediate phenotypes of schizophrenia in Sp4 hypomorphic mice. Recent human genetic studies from both the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) and the Genome-Wide Association Study (GWAS) validated SP4 as a schizophrenia-risk gene over the exome-wide or the genome-wide significance. Truncation of the human SP4 gene has an odds ratio of 9.37 (3.38–29.7) for schizophrenia. Despite successful identification of many schizophrenia-risk genes, it is unknown whether and how these risk genes may interact with each other in the development of schizophrenia. By taking advantage of the specific localization of the GC-boxes bound by SP4 transcription factors, I analyzed the relative abundance of these GC-boxes in the proximal promoter regions of schizophrenia-risk genes. I found that the GC-box containing genes are significantly over-represented within schizophrenia-risk genes, suggesting that SP4 is not only a high-risk gene for schizophrenia, but may also act as a hub of network in the regulation of many other schizophrenia-risk genes via these GC-boxes in the pathogenesis of schizophrenia.
Highlights
Sp4, a homolog of the Drosophila buttonhead gene, belongs to the Sp1 family of transcription factors [1]
The 100 nucleotide (−140,−41, red line) window for the GC-box is similar to the (−130,−30) window in previous studies [16] and slightly larger than Kadonaga’s (−100,−40) window in early studies, likely due to more accurate transcription start site (TSS) mapping of many thousands of genes in the most recent Eukaryotic promoter database (EPD) database
Out of the top ten high-risk genes, Sp4 and RB1CC1, the only two DNA-binding transcription factors, bind the same GC-box in regulation of genes involved in the pathogenesis of schizophrenia
Summary
Sp4, a homolog of the Drosophila buttonhead (btd) gene, belongs to the Sp1 family of transcription factors [1]. Sp1, a ubiquitous transcription factor, recognizes the DNA sequence 5ʹ-GGGCGG-3ʹ termed GC-box that is often found ~40–100 nucleotides upstream of the transcription start site (TSS) of a variety of genes and is critical for activation of their expression [2]. Both Sp1 and Sp4 bind the same GCbox with the same affinity [3]. We found that reduction of Sp4 expression in Sp4 hypomorphic mice causes age-dependent hippocampal vacuolization, reduced hippocampal LTP, and many behavioral abnormalities related to schizophrenia such as deficits in prepulse inhibition, deficient learning and memory, hypersensitivity to NMDAR antagonists, etc. We and Tam et al first reported that the human SP4 gene is sporadically deleted in schizophrenia patients [6, 10]
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