A Functional Variant Rs492554 Associated With Congenital Heart Defects Modulates SESN2 Expression Through POU2F1.

Wenke Yang,Jun Bai,Yi Li,Tao You,Kang Yi,Xiaowei Zhang,Xiaowei Zhang,Dingxiong Xie,Xiaodong Xie

doi:10.3389/fcell.2021.668474

Abstract

Hypoxia exposure is responsible for the high incidence of congenital heart defects (CHDs) in high-altitude areas, which is nearly 20 times higher than that in low-altitude areas. However, the genetic factors involved are rarely reported. Sestrin2 (SESN2), a hypoxia stress-inducible gene, protects cardiomyocyte viability under stress; thus, SESN2 polymorphism may be a potential risk factor for CHD. We performed an association study of the SESN2 polymorphisms with CHD risk in two independent groups of the Han Chinese population from two different altitude areas. The allele-specific effects of lead single-nucleotide polymorphisms (SNPs) were assessed by expression quantitative trait locus, electrophoretic mobility shift, and luciferase reporter assays. The molecular mechanism of Sesn2 action against hypoxia-induced cell injury was investigated in embryonic rat-heart-derived H9c2 cells treated with or without hypoxia-mimetic cobalt chloride. SNP rs492554 was significantly associated with reduced CHD risk in the high-altitude population, but not in the low-altitude population. The protective T allele of rs492554 was correlated with higher SESN2 expression and showed a preferential binding affinity to POU2F1. We then identified SNP rs12406992 in strong linkage disequilibrium with rs492554 and mapped it within the binding motif of POU2F1. The T-C haplotype of rs492554-rs12406992 could increase luciferase expression, whereas POU2F1 knockdown effectively suppressed it. Mechanistically, increased Sesn2 protects against oxidative stress and cell apoptosis and maintains cell viability and proliferation. In summary, CHD-associated SNP rs492554 acts as an allele-specific distal enhancer to modulate SESN2 expression via interaction with POU2F1, which might provide new mechanistic insights into CHD pathogenesis.

Highlights

Congenital heart defects (CHD), structural heart defects caused by abnormal cardiovascular development during the embryonic period, are one of the most common congenital malformations in humans and the main non-infectious cause of infant death (Schneider et al, 2004; van der Linde et al, 2011)
We present a study for understanding the mechanism underlying the rs492554 CHD protective locus related to high-altitude hypoxic environment exposure from the perspective of genetic factors
Our study provides evidence that rs492554 is associated with CHD susceptibility in high-altitude populations and has an expression quantitative trait locus (eQTL) effect on the downstream hypoxia response gene SESN2

Summary

Introduction

Congenital heart defects (CHD), structural heart defects caused by abnormal cardiovascular development during the embryonic period, are one of the most common congenital malformations in humans and the main non-infectious cause of infant death (Schneider et al, 2004; van der Linde et al, 2011). The incidence of CHD in high-altitude areas is 20 times higher than that in low-altitude areas, mainly owing to exposure to high-altitude hypoxic environments The etiology of CHD involves environmental and genetic factors and their interaction (Hinton, 2013), studies on genetic factors involved in hypoxic environment exposure have been rarely reported. SESN2 protein has two known independent functional domains, including an N-terminal oxidoreductase domain with antioxidant activity and a C-terminal domain that inhibits the mTOR signaling pathway (Kim et al, 2015). Through these two molecular functions, SESN2 exhibits cytoprotective effects in response to aberrant cellular stress. SESN2 exerts a cardioprotective effect against damage caused by lipopolysaccharide, doxorubicin, and aging (Hwang et al, 2018; Li R. et al, 2019; Liu et al, 2020); its role in heart development remains unclear

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