title: Modulation of transcription factor binding and epigenetic regulation of the MLH1 CpG island and shore by polymorphism rs1800734 in colorectal cancer.
abstract: The MLH1 promoter polymorphism rs1800734 is associated with MLH1 CpG island hypermethylation and expression loss in colorectal cancer (CRC). Conversely, variant rs1800734 is associated with MLH1 shore, but not island, hypomethylation in peripheral blood mononuclear cell DNA. To explore these distinct patterns, MLH1 CpG island and shore methylation was assessed in CRC cell lines stratified by rs1800734 genotype. Cell lines containing the variant A allele demonstrated MLH1 shore hypomethylation compared to wild type (GG). There was significant enrichment of transcription factor AP4 at the MLH1 promoter in GG and GA cell lines, but not the AA cell line, by chromatin immunoprecipitation studies. Preferential binding to the G allele was confirmed by sequencing in the GA cell line. The enhancer-associated histone modification H3K4me1 was enriched at the MLH1 shore; however, H3K27ac was not, indicating the shore is an inactive enhancer. These results demonstrate the role of variant rs1800734 in altering transcription factor binding as well as epigenetics at regions beyond the MLH1 CpG island in which it is located.
authors.affiliation: a Lunenfeld-Tanenbaum Research Institute, Sinai Health System , Toronto , Ontario , Canada.|b Department of Laboratory Medicine and Pathobiology , University of Toronto , Toronto , Ontario , Canada.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Savio
authors.affiliation: a Lunenfeld-Tanenbaum Research Institute, Sinai Health System , Toronto , Ontario , Canada.|b Department of Laboratory Medicine and Pathobiology , University of Toronto , Toronto , Ontario , Canada.|c Department of Pathology , University Health Network , Toronto , Ontario , Canada.
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D014157:Transcription Factors; D000070957:MutL Protein Homolog 1
keywords: Chromatin immunoprecipitation; DNA methylation; DNA mismatch repair; colorectal cancer; histone modifications; mutL homolog 1; single nucleotide polymorphisms