The osteoporosis susceptibility SNP rs188303909 at 2q14.2 regulates EN1 expression by modulating DNA methylation and E2F6 binding

In this study, we identified rs188303909, a functional CpG-SNP, as a causal SNP for osteoporosis at 2q14.2 through the integration of functional and epigenomic analyses. Functional experiments demonstrated that unmethylated rs188303909 acted as a strong allele-specific distal enhancer to regulateEN1 expression by modifying the binding of transcription factor E2F6, but rs188303909 methylation attenuated the active effect of E2F6 onEN1 expression. Importantly, transcription factor EN1 could differentially bind osteoporosis GWAS lead SNPs rs4869739-T and rs4355801-G to upregulateCCDC170 andCOLEC10 expression, thus promoting bone formation. Our study provided a mechanistic insight into expression regulation of the osteoporosis susceptibility geneEN1, which could be a potential therapeutic target for osteoporosis precision medicine.Key messagesCpG-SNP rs188303909 is a causal SNP at the osteoporosis susceptibility locus 2q14.2.Rs188303909 distally regulates  EN1 expression by modulating DNA methylation and E2F6 binding.EN1 upregulates  CCDC170 andCOLEC10 expression through osteoporosis GWAS lead SNPs rs4869739 and rs4355801.
Source: Journal of Molecular Medicine - Category: Molecular Biology Source Type: research