title: Interaction between genetic and epigenetic variation defines gene expression patterns at the asthma-associated locus 17q12-q21 in lymphoblastoid cell lines.
abstract: Phenotypic variation results from variation in gene expression, which is modulated by genetic and/or epigenetic factors. To understand the molecular basis of human disease, interaction between genetic and epigenetic factors needs to be taken into account. The asthma-associated region 17q12-q21 harbors three genes, the zona pellucida binding protein 2 (ZPBP2), gasdermin B (GSDMB) and ORM1-like 3 (ORMDL3), that show allele-specific differences in expression levels in lymphoblastoid cell lines (LCLs) and CD4+ T cells. Here, we report a molecular dissection of allele-specific transcriptional regulation of the genes within the chromosomal region 17q12-q21 combining in vitro transfection, formaldehyde-assisted isolation of regulatory elements, chromatin immunoprecipitation and DNA methylation assays in LCLs. We found that a single nucleotide polymorphism rs4795397 influences the activity of ZPBP2 promoter in vitro in an allele-dependent fashion, and also leads to nucleosome repositioning on the asthma-associated allele. However, variable methylation of exon 1 of ZPBP2 masks the strong genetic effect on ZPBP2 promoter activity in LCLs. In contrast, the ORMDL3 promoter is fully unmethylated, which allows detection of genetic effects on its transcription. We conclude that the cis-regulatory effects on 17q12-q21 gene expression result from interaction between several regulatory polymorphisms and epigenetic factors within the cis-regulatory haplotype region.
authors.affiliation: Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada.
authors.forename: Soizik
authors.initials: S
authors.lastname: Berlivet
authors.forename: Sanny
authors.initials: S
authors.lastname: Moussette
authors.forename: Manon
authors.initials: M
authors.lastname: Ouimet
authors.forename: Dominique J
authors.initials: DJ
authors.lastname: Verlaan
authors.forename: Vonda
authors.initials: V
authors.lastname: Koka
authors.forename: Abeer
authors.initials: A
authors.lastname: Al Tuwaijri
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.forename: Anna K
authors.initials: AK
authors.lastname: Naumova
mesh_terms: D001249:Asthma / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D019175:DNA Methylation; D004527:Egg Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D000094524:Gasdermins
chemical_list: D004527:Egg Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C527978:GSDMB protein, human; D000094524:Gasdermins; C464399:ORMDL3 protein, human; C479482:ZPBP2 protein, human