posted on 2021-05-26, 14:19authored byShan-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.