TY - JOUR
T1 - A Novel Polymorphic AP-1 Binding Element of the GFAP Promoter is Associated with Different Allelic Transcriptional Activities
AU - Bachetti, Tiziana
AU - DiZanni, Eleonora
AU - Lantieri, Francesca
AU - Caroli, Francesco
AU - Regis, Stefano
AU - Filocamo, Mirella
AU - Rainero, Innocenzo
AU - Gallone, Salvatore
AU - Cilia, Roberto
AU - Romano, Silvia
AU - Savoiardo, Mario
AU - Pareyson, Davide
AU - Biancheri, Roberta
AU - Ravazzolo, Roberto
AU - Ceccherini, Isabella
PY - 2010/11
Y1 - 2010/11
N2 - The Glial Fibrillary Acidic Protein (GFAP) gene encodes a cytoskeletal protein belonging to the intermediate filament family whose expression is considered as a marker of astrocytes differentiation. GFAP expression, shown to be upregulated as a consequence of brain gliosis, depends on hormones, growth factors, cytokine, and transcription factors and, among these latters, activator protein 1 (AP-1) has been demonstrated to play a crucial role. In this study, we have focused on a 2.2 kb sequence of the regulatory region located upstream of the GFAP gene, searching in a panel of control individuals for single-nucleotide polymorphisms (SNPs) that could modulate GFAP transcription. Among four SNPs of the GFAP promoter whose alleles have been predicted by in silico analysis to induce differences in the pattern of binding transcription factors, we have identified a new AP-1 binding site lying at -250 bp upstream from the GFAP transcriptional start site. The two alleles of this polymorphic locus have shown to bind the AP-1 complex to different extents, thus promoting variable transcriptional activities of the GFAP promoter. Therefore, these SNP alleles may, among others, mediate the effects of GFAP mutations, thus explaining the phenotypic heterogeneity of Alexander disease.
AB - The Glial Fibrillary Acidic Protein (GFAP) gene encodes a cytoskeletal protein belonging to the intermediate filament family whose expression is considered as a marker of astrocytes differentiation. GFAP expression, shown to be upregulated as a consequence of brain gliosis, depends on hormones, growth factors, cytokine, and transcription factors and, among these latters, activator protein 1 (AP-1) has been demonstrated to play a crucial role. In this study, we have focused on a 2.2 kb sequence of the regulatory region located upstream of the GFAP gene, searching in a panel of control individuals for single-nucleotide polymorphisms (SNPs) that could modulate GFAP transcription. Among four SNPs of the GFAP promoter whose alleles have been predicted by in silico analysis to induce differences in the pattern of binding transcription factors, we have identified a new AP-1 binding site lying at -250 bp upstream from the GFAP transcriptional start site. The two alleles of this polymorphic locus have shown to bind the AP-1 complex to different extents, thus promoting variable transcriptional activities of the GFAP promoter. Therefore, these SNP alleles may, among others, mediate the effects of GFAP mutations, thus explaining the phenotypic heterogeneity of Alexander disease.
KW - AP-1
KW - GFAP promoter
KW - Single nucleotide polymorphisms
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U2 - 10.1111/j.1469-1809.2010.00614.x
DO - 10.1111/j.1469-1809.2010.00614.x
M3 - Article
C2 - 20946255
AN - SCOPUS:77958180258
VL - 74
SP - 506
EP - 515
JO - Annals of Human Genetics
JF - Annals of Human Genetics
SN - 0003-4800
IS - 6
ER -