4.6 Article

GATA4 and estrogen receptor alpha bind at SNPs rs9921222 and rs10794639 to regulate AXIN1 expression in osteoblasts

Journal

HUMAN GENETICS
Volume 141, Issue 12, Pages 1849-1861

Publisher

SPRINGER
DOI: 10.1007/s00439-022-02463-8

Keywords

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Funding

  1. Development and Promotion of Science and Technology Talents Project scholarship from the Royal Government of Thailand
  2. Alma and Hal Reagan Endowment Fellowship at UTHSC

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This study reveals the molecular mechanism of SNP rs9921222 in regulating the expression of AXIN1 in human osteoblasts through GATA4 and ER alpha binding. The findings provide important insights into the genetic mechanism underlying osteoporosis and bone density regulation.
Osteoporosis is a serious public health problem that affects 200 million people worldwide. Genome-wide association studies have revealed the association between several single nucleotide polymorphisms (SNPs) near WNT/beta-catenin signaling genes and bone mineral density (BMD). The activation of beta-catenin by WNT ligands is required for osteoblast differentiation. SNP rs9921222 is an intronic variant of AXIN1 (a scaffold protein in the destruction complex that regulates beta-catenin signaling) that correlates with BMD. However, the biological mechanism of SNP rs9921222 has never been reported. Here, we show that the genotype of SNP rs9921222 correlates with the expression of AXIN1 in human osteoblasts. RNA and genomic DNA were analyzed from primary osteoblasts from 111 different individuals. Homozygous TT at rs9921222 correlates with a higher expression of AXIN1 than homozygous CC. Regional association analysis showed that rs9921222 is in high linkage disequilibrium (LD) with SNP rs10794639. In silico transcription factor analysis predicted that rs9921222 is within a GATA4 motif and rs10794639 is adjacent to an estrogen receptor alpha (ER alpha) motif. Mechanistically, GATA4 and ER alpha bind at SNPs rs9921222 and rs10794639 as detected by ChIP-qPCR. Luciferase assays demonstrate that rs9921222 is the causal SNP to alter ER alpha and GATA4 binding. GATA4 promoted the expression, and in contrast, ER alpha suppressed the expression of AXIN1 via the histone deacetylase complex member SIN3A. Functionally, the level of AXIN1 negatively correlates with the level of transcriptionally active beta-catenin. In summary, we have discovered a molecular mechanism of the SNP rs9921222 to regulate AXIN1 through GATA4 and ER alpha binding in human osteoblasts.

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