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LncRNA ZBTB40-IT1 modulated by osteoporosis GWAS risk SNPs suppresses osteogenesis
Bing Mei1, Ya Wang1, Weiyuan Ye1
1Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 430079, China.
Abstract:
Previous genome-wide linkage and association studies have identified an osteoporosis-associated locus at 1p36 that harbors SNPs rs34920465 and rs6426749. The 1p36 locus also comprises the WNT4 gene with known role in bone metabolism and functionally unknown ZBTB40/lncRNA ZBTB40-IT1 genes. How these might interact to contribute to osteoporosis susceptibility is not known. In this study, we show that lncRNA ZBTB40-IT1 is able to suppress osteogenesis and promote osteoclastogenesis by regulating the expression of WNT4, RUNX2, OSX, ALP, COL1A1, OPG and RANKL in U-2OS and hFOB1.19 cell lines, whereas ZBTB40 plays an opposite role in bone metabolism. Treatment with parathyroid hormone significantly downregulates the expression of ZBTB40-IT1 in U-2OS cell lines. ZBTB40 can suppress ZBTB40-IT1 expression but has no response to parathyroid hormone treatment. Dual-luciferase assay and biotin pull-down assay demonstrate that osteoporosis GWAS lead SNPs rs34920465-G and rs6426749-C alleles can respectively bind transcription factors JUN::FOS and CREB1, and upregulate ZBTB40 and ZBTB40-IT1 expression. Our study discovers the critical role of ZBTB40 and lncRNA ZBTB40-IT1 in bone metabolism, and provides a mechanistic basis for osteoporosis GWAS lead SNPs rs34920465 and rs6426749.
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