Nrf2 pre‐recruitment at Enhancer 2 is a hallmark of H2O2‐induced epigenetic transcriptional memory in the HMOX1 gene in human umbilical artery endothelial cells

Author:

Carrasco‐Wong Ivo1ORCID,Längst Gernot2,Sobrevia Luis34567ORCID,Casanello Paola789ORCID

Affiliation:

1. Cellular Signaling and Differentiation Laboratory (CSDL), School of Medical Technology, Medicine and Science Faculty Universidad San Sebastian Santiago Chile

2. Biochemistry III, Biochemistry Centre Regensburg (BCR) University of Regensburg Regensburg Germany

3. Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynecology, School of Medicine, Faculty of Medicine Pontificia Universidad Católica de Chile Santiago Chile

4. Department of Physiology, Faculty of Pharmacy Universidad de Sevilla Seville Spain

5. Medical School, Faculty of Medicine Sao Paulo State University (UNESP) Sao Paulo Sao Paulo Brazil

6. University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences University of Queensland, Herston Brisbane Queensland Australia

7. Division of Pathology, Department of Pathology and Medical Biology University of Groningen, University Medical Center Groningen (UMCG) Groningen the Netherlands

8. Department of Neonatology, School of Medicine Pontificia Universidad Católica de Chile Santiago Chile

9. Department of Obstetrics, School of Medicine Pontificia Universidad Católica de Chile Santiago Chile

Abstract

AbstractMaternal obesity (MO) is a significant cause of increased cardiometabolic risk in offspring, who present endothelial dysfunction at birth. Alterations in physiologic and cellular redox status are strongly associated with altered gene regulation in arterial endothelium. However, specific mechanisms by which the pro‐oxidant fetal environment in MO could modulate the vascular gene expression and function during the offspring's postnatal life are elusive. We tested if oxidative stress could reprogram the antioxidant‐coding gene's response to a pro‐oxidant challenge through an epigenetic transcriptional memory (ETM) mechanism. A pro‐oxidant double‐hit protocol was applied to human umbilical artery endothelial cells (HUAECs) and EA.hy 926 endothelial cell lines. The ETM acquisition in the HMOX1 gene was analyzed by RT‐qPCR. HMOX1 mRNA decay was evaluated by Actinomycin‐D treatment and RT‐qPCR. To assess the chromatin accessibility and the enrichment of NRF2, RNAP2, and phosphorylation at serin‐5 of RNAP2, at HMOX1 gene regulatory regions, were used DNase HS‐qPCR and ChIP‐qPCR assays, respectively. The CpG methylation pattern at the HMOX1 core promoter was analyzed by DNA bisulfite conversion and Sanger sequencing. Data were analyzed using two‐way ANOVA, and p < 0.05 was statistically significant. Using a pro‐oxidant double‐hit protocol, we found that the Heme Oxygenase gene (HMOX1) presents an ETM response associated with changes in the chromatin structure at the promoter and gene regulatory regions. The ETM response was characterized by a paused‐RNA Polymerase 2 and NRF2 enrichment at the transcription start site and Enhancer 2 of the HMOX1 gene, respectively. Changes in DNA methylation pattern at the HMOX1 promoter were not a hallmark of this oxidative stress‐induced ETM. These data suggest that a pro‐oxidant milieu could trigger an ETM at the vascular level, indicating a potential epigenetic mechanism involved in the increased cardiovascular risk in the offspring of women with obesity.

Publisher

Wiley

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