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An Intronic Risk SNP rs12454712 for Central Obesity Acts as an Allele-Specific Enhancer to Regulate BCL2 Expression

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posted on 26.05.2021, 14:19 by Shan-Shan Dong, Dong-Li Zhu, Xiao-Rong Zhou, Yu Rong, Mengqi Zeng, Jia-Bin Chen, Feng Jiang, Xiao-Mei Tuo, Zhihui Feng, Tie-Lin Yang, Yan Guo
Genome-wide association studies (GWASs) have reproducibly associated the SNP rs12454712 with waist-to-hip ratio adjusted for body mass index (WHRadjBMI), but the functional role underlying this intronic variant is unknown. Integrative genomic and epigenomic analyses supported rs12454712 as a functional independent variant. We further demonstrated that rs12454712 acted as an allele-specific enhancer regulating expression of its located gene BCL2 by using dual-luciferase reporter assays and CRISPR-Cas9. Specifically, rs12454712-C allele can bind transcription factor ZNF329, which efficiently elevates the enhancer activity and increases BCL2 expression. Knocking down Bcl2 in 3T3-L1 cells led to the down-regulation of adipogenic differentiation marker genes and increased cell apoptosis. Significant negative correlation between BCL2 expression in subcutaneous adipose tissues and obesity was observed. Our findings illustrate the molecular mechanisms behind the intronic SNP rs12454712 for central obesity, which would be a potential and promising target for developing appropriate therapies.

Funding

This study is supported by the National Natural Science Foundation of China (32070588, 31871264), Natural Science Basic Research Program of Shaanxi (2021JC-02), Natural Science Foundation of Zhejiang Province (LWY20H060001), China Postdoctoral Science Foundation (2020M683454), and the Fundamental Research Funds for the Central Universities.

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