Single nucleotide polymorphisms rs148582811 regulates its host gene ARVCF expression to affect nicotine-associated hippocampus-dependent memory

Zhongli Yang; Jiali Chen; Haijun Han; Yan Wang; Xiaoqiang Shi; Bin Zhang; Ying Mao; Andria N Li; Wenji Yuan; Jianhua Yao; Ming D Li

doi:10.1016/j.isci.2023.108335

Single nucleotide polymorphisms rs148582811 regulates its host gene ARVCF expression to affect nicotine-associated hippocampus-dependent memory

iScience. 2023 Oct 28;26(12):108335. doi: 10.1016/j.isci.2023.108335. eCollection 2023 Dec 15.

Authors

Zhongli Yang^{1

2}, Jiali Chen¹, Haijun Han¹, Yan Wang¹, Xiaoqiang Shi¹, Bin Zhang¹, Ying Mao¹, Andria N Li³, Wenji Yuan¹, Jianhua Yao², Ming D Li^{1

4}

Affiliations

¹ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
² Joint Institute of Smoking and Health, Kunming, Yunnan 650024, China.
³ Vanderbilt University School of Medicine, Nashville, TN 37240, USA.
⁴ Research Center for Air Pollution and Health, Zhejiang University, Hangzhou 310058, China.

Abstract

Although numerous susceptibility loci are nominated for nicotine dependence (ND), no report showed any association of ARVCF with ND. Through genome-wide sequencing analysis, we first identified genetic variants associated nominally with ND and then replicated them in an independent sample. Of the six replicated variants, rs148582811 in ARVCF located in the enhancer-associated marker peak is attractive. The effective-median-based Mendelian randomization analysis indicated that ARVCF is a causal gene for ND. RNA-seq analysis detected decreased ARVCF expression in smokers compared to nonsmokers. Luciferase reporter assays indicated that rs148582811 and its located DNA fragment allele-specifically regulated ARVCF expression. Immunoprecipitation analysis revealed that transcription factor X-ray repair cross-complementing protein 5 (XRCC5) bound to the DNA fragment containing rs148582811 and allele-specifically regulated ARVCF expression at the mRNA and protein levels. With the Arvcf knockout mouse model, we showed that Arvcf deletion not only impairs hippocampus-dependent learning and memory, but also alleviated nicotine-induced memory deficits.

Keywords: Behavioral neuroscience; Biological sciences; Clinical neuroscience; Natural sciences; Neuroscience.