Modulation of transcription factor binding and epigenetic regulation of the <i>MLH1</i> CpG island and shore by polymorphism rs1800734 in colorectal cancer

2017-03-17T14:37:48Z (GMT) by Andrea J. Savio Bharati Bapat
<p>The <i>MLH1</i> promoter polymorphism rs1800734 is associated with <i>MLH1</i> CpG island hypermethylation and expression loss in colorectal cancer (CRC). Conversely, variant rs1800734 is associated with <i>MLH1</i> shore, but not island, hypomethylation in peripheral blood mononuclear cell DNA. To explore these distinct patterns, <i>MLH1</i> CpG island and shore methylation was assessed in CRC cell lines stratified by rs1800734 genotype. Cell lines containing the variant A allele demonstrated <i>MLH1</i> shore hypomethylation compared to wild type (GG). There was significant enrichment of transcription factor AP4 at the <i>MLH1</i> 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 <i>MLH1</i> 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 <i>MLH1</i> CpG island in which it is located.</p>