title: The rs3743205 SNP is important for the regulation of the dyslexia candidate gene DYX1C1 by estrogen receptor β and DNA methylation.
abstract: Estrogen is involved in numerous physiological processes such as growth, differentiation, and function of the male and female reproductive tissues. In the developing brain, estrogen signaling has been linked to cognitive functions, such as learning and memory; however, the molecular mechanisms underlying this phenomenon are poorly understood. We have previously shown a link between developmental dyslexia and estrogen signaling, when we studied the functional interactions between the dyslexia candidate protein DYX1C1 and the estrogen receptors α (ERα) and β (ERβ). Here, we investigate the 17β-estradiol (E2)-dependent regulation of dyslexia susceptibility 1 candidate 1 (DYX1C1) expression. We demonstrate that ERβ, not ERα, binds to a transcriptionally active cis-regulatory region upstream of DYX1C1 transcriptional start site and that DYX1C1 expression is enhanced by E2 in a neuroblastoma cell line. This regulation is dependent on transcription factor II-I and liganded ERβ recruitment to this region. In addition, we describe that a single nucleotide polymorphism previously shown to be associated with dyslexia and located in the cis-regulatory region of DYX1C1 may alter the epigenetic and endocrine regulation of this gene. Our data provide important molecular insights into the relationship between developmental dyslexia susceptibility and estrogen signaling.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE-14183 Huddinge, Sweden.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Tammimies
authors.forename: Isabel
authors.initials: I
authors.lastname: Tapia-Páez
authors.forename: Joëlle
authors.initials: J
authors.lastname: Rüegg
authors.forename: Gustaf
authors.initials: G
authors.lastname: Rosin
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: Ivan
authors.initials: I
authors.lastname: Nalvarte
mesh_terms: D020121:5' Untranslated Regions; D045744:Cell Line, Tumor; D018387:Codon, Initiator / Q000235:genetics; D003598:Cytoskeletal Proteins; D019175:DNA Methylation; D004410:Dyslexia / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D004958:Estradiol / Q000502:physiology; D047629:Estrogen Receptor beta / Q000378:metabolism / Q000502:physiology*; D004967:Estrogens / Q000502:physiology; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D020218:Response Elements; D019473:Transcription Factors, TFII / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D018387:Codon, Initiator; D003598:Cytoskeletal Proteins; C478878:DNAAF4 protein, human; D047629:Estrogen Receptor beta; D004967:Estrogens; C104259:GTF2I protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019473:Transcription Factors, TFII; D004958:Estradiol