The complex of TFII-I, PARP1, and SFPQ proteins regulates the DYX1C1 gene implicated in neuronal migration and dyslexia.
DYX1C1 was first identified as a candidate gene for dyslexia susceptibility, and its role in controlling neuronal migration during embryogenesis and effect on learning in rodents have been verified. In contrast, genetic association studies have been ambiguous in replicating its effects on dyslexia. To better understand the regulation of DYX1C1 and the possible functional role of genetic variation in the promoter of DYX1C1, we selected three single-nucleotide polymorphisms (SNPs) with predicted functional consequences or suggested associations to dyslexia for detailed study. Electrophoretic mobility shift assays suggested the allele-specific binding of the transcription factors TFII-I (to rs3743205) and Sp1 (to rs16787 and rs12899331) that could be verified by competition assays. In addition, we purified a complex of protein factors binding to the previously suggested dyslexia-related SNP, -3G/A (rs3743205). Three proteins, TFII-I, PARP1, and SFPQ, were unambiguously identified by mass spectrometry and protein sequencing. Two SNPs, rs16787 and rs3743205, showed significant allelic differences in luciferase assays. Our results show that TFII-I, PARP1, and SFPQ proteins, each previously implicated in gene regulation, form a complex controlling transcription of DYX1C1. Furthermore, allelic differences in the promoter or 5' untranslated region of DYX1C1 may affect factor binding and thus regulation of the gene.
Tapia-Páez
Isabel
I
Department of Biosciences and Nutrition, 141 57 Huddinge, Karolinska Institute, Stockholm, Sweden.
Tammimies
Kristiina
K
Massinen
Satu
S
Roy
Ananda L
AL
Kere
Juha
J
D020121:5' Untranslated Regions; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D003598:Cytoskeletal Proteins; D017931:DNA Primers / Q000235:genetics; D004410:Dyslexia / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology*; D000072670:PTB-Associated Splicing Factor; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019473:Transcription Factors, TFII / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D020121:5' Untranslated Regions; D003598:Cytoskeletal Proteins; D017931:DNA Primers; C478878:DNAAF4 protein, human; C104259:GTF2I protein, human; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000072670:PTB-Associated Splicing Factor; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D019473:Transcription Factors, TFII; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases