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

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 ca...

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Main Authors: Wenke Yang, Yi Li, Jun Bai, Tao You, Kang Yi, Dingxiong Xie, Xiaowei Zhang, Xiaodong Xie
Format: Article
Language:English
Published: Frontiers Media S.A. 2021-06-01
Series:Frontiers in Cell and Developmental Biology
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Online Access:https://www.frontiersin.org/articles/10.3389/fcell.2021.668474/full
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spelling doaj-91a86029783d47ba93802cc6e8325cd82021-06-23T05:14:17ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-06-01910.3389/fcell.2021.668474668474A Functional Variant Rs492554 Associated With Congenital Heart Defects Modulates SESN2 Expression Through POU2F1Wenke Yang0Wenke Yang1Yi Li2Yi Li3Jun Bai4Jun Bai5Tao You6Kang Yi7Dingxiong Xie8Xiaowei Zhang9Xiaodong Xie10Xiaodong Xie11Xiaodong Xie12Institute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaGansu Cardiovascular Institute, People’s Hospital of Lanzhou City, Lanzhou, ChinaInstitute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaSchool/Hospital of Stomatology, Lanzhou University, Lanzhou, ChinaInstitute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaDepartment of Hematology, Gansu Provincial Key Laboratory of Hematology, Second Hospital of Lanzhou University, Lanzhou, ChinaDepartment of Cardiac Surgery, Gansu Provincial Hospital, Lanzhou, ChinaDepartment of Cardiac Surgery, Gansu Provincial Hospital, Lanzhou, ChinaGansu Cardiovascular Institute, People’s Hospital of Lanzhou City, Lanzhou, ChinaDepartment of Hematology, Gansu Provincial Key Laboratory of Hematology, Second Hospital of Lanzhou University, Lanzhou, ChinaInstitute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaGansu Cardiovascular Institute, People’s Hospital of Lanzhou City, Lanzhou, ChinaGenetics Medicine Center, Gansu Provincial Maternity and Child-Care Hospital, Lanzhou, ChinaHypoxia 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.668474/fullcongenital heart defectsSESN2 genesingle nucleotide polymorphismsrs492554high-altitudehypoxia
collection DOAJ
language English
format Article
sources DOAJ
author Wenke Yang
Wenke Yang
Yi Li
Yi Li
Jun Bai
Jun Bai
Tao You
Kang Yi
Dingxiong Xie
Xiaowei Zhang
Xiaodong Xie
Xiaodong Xie
Xiaodong Xie
spellingShingle Wenke Yang
Wenke Yang
Yi Li
Yi Li
Jun Bai
Jun Bai
Tao You
Kang Yi
Dingxiong Xie
Xiaowei Zhang
Xiaodong Xie
Xiaodong Xie
Xiaodong Xie
A Functional Variant Rs492554 Associated With Congenital Heart Defects Modulates SESN2 Expression Through POU2F1
Frontiers in Cell and Developmental Biology
congenital heart defects
SESN2 gene
single nucleotide polymorphisms
rs492554
high-altitude
hypoxia
author_facet Wenke Yang
Wenke Yang
Yi Li
Yi Li
Jun Bai
Jun Bai
Tao You
Kang Yi
Dingxiong Xie
Xiaowei Zhang
Xiaodong Xie
Xiaodong Xie
Xiaodong Xie
author_sort Wenke Yang
title A Functional Variant Rs492554 Associated With Congenital Heart Defects Modulates SESN2 Expression Through POU2F1
title_short A Functional Variant Rs492554 Associated With Congenital Heart Defects Modulates SESN2 Expression Through POU2F1
title_full A Functional Variant Rs492554 Associated With Congenital Heart Defects Modulates SESN2 Expression Through POU2F1
title_fullStr A Functional Variant Rs492554 Associated With Congenital Heart Defects Modulates SESN2 Expression Through POU2F1
title_full_unstemmed A Functional Variant Rs492554 Associated With Congenital Heart Defects Modulates SESN2 Expression Through POU2F1
title_sort functional variant rs492554 associated with congenital heart defects modulates sesn2 expression through pou2f1
publisher Frontiers Media S.A.
series Frontiers in Cell and Developmental Biology
issn 2296-634X
publishDate 2021-06-01
description 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.
topic congenital heart defects
SESN2 gene
single nucleotide polymorphisms
rs492554
high-altitude
hypoxia
url https://www.frontiersin.org/articles/10.3389/fcell.2021.668474/full
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