title: Characterization of human collagen XVIII promoter 2: interaction of Sp1, Sp3 and YY1 with the regulatory region and a SNP that increases transcription in hepatocytes.
abstract: Different levels of Collagen XVIII expression have been associated with several pathological processes such as cancer, liver fibrosis, diabetic retinopathy and Alzheimer's disease. Understanding the transcriptional regulation of Collagen XVIII might elucidate some pathways related to the progression of these diseases. The promoter 2 of COL18A1 gene is poorly understood and is responsible for the transcription of this gene in several adult tissues such as liver, eyes and brain. This study focused upon characterization of cis-regulatory elements interacting with human COL18A1 promoter 2 and identification of SNPs in this region in different ethnic groups. Our results show that there are five conserved regions (I to V) between human and mouse promoter 2 and that the human COL18A1 core promoter is located between nucleotides -186 and -21. Sp1 and Sp3 bind to conserved regions I and V, while Sp3 and YY1 interact with region II. We have verified that the SNP at position -700 (T>G) is embedded in two common haplotypes, which have different frequencies between European and African descendents. The allele -700G increases transcription and binding for a still unknown transcription factor. SNP -700 affects Sp3 and YY1 interaction with this region, even though it is not part of these transcription factors' predicted binding sites. Therefore, our results show for the first time that Sp3 and YY1 interact with human COL18A1 promoter 2, and that nucleotide -700 is part of a binding motif for a still unknown TF that is involved in the expression of this gene in hepatocytes. In addition, we also confirm the involvement of Sp1 in the regulation of this gene.
authors.affiliation: Department of Genetics and Evolution Biology , Bioscience Institute, University of São Paulo, Brazil.
authors.forename: Lucia M
authors.initials: LM
authors.lastname: Armelin-Correa
authors.forename: Chin J
authors.initials: CJ
authors.lastname: Lin
authors.forename: Angela
authors.initials: A
authors.lastname: Barbosa
authors.forename: Kelly
authors.initials: K
authors.lastname: Bagatini
authors.forename: Sheila M B
authors.initials: SM
authors.lastname: Winnischofer
authors.forename: Mari C
authors.initials: MC
authors.lastname: Sogayar
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Passos-Bueno
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D043170:Collagen Type XVIII / Q000235:genetics*; D017124:Conserved Sequence; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009698:Nucleoproteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D020218:Response Elements / Q000235:genetics; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D050986:YY1 Transcription Factor / Q000378:metabolism*
chemical_list: D043170:Collagen Type XVIII; D009698:Nucleoproteins; D016329:Sp1 Transcription Factor; D050986:YY1 Transcription Factor; D051705:Sp3 Transcription Factor