Gene-environment regulation of chamber-specific maturation during hypoxemic perinatal circulatory transition
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ORIGINAL ARTICLE
Gene-environment regulation of chamber-specific maturation during hypoxemic perinatal circulatory transition Yan Zhao 1,2 & Xuedong Kang 1,2 & Alexander Barsegian 1,2 & Jian He 1,2 & Alejandra Guzman 1,2 & Ryan P. Lau 3 & Reshma Biniwale 4 & Madhuri Wadhra 3 & Brian Reemtsen 4 & Meena Garg 1 & Nancy Halnon 1 & Fabiola Quintero-Rivera 3 & Wayne W. Grody 3 & the UCLA Congenital Heart Defects BioCore Faculty & Glen Van Arsdell 4 & Stanley F. Nelson 1,5,6,10 & Marlin Touma 1,2,6,7,8,9,10 Received: 17 January 2020 / Revised: 12 May 2020 / Accepted: 28 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Chamber-specific and temporally regulated perinatal cardiac growth and maturation is critical for functional adaptation of the heart and may be altered significantly in response to perinatal stress, such as systemic hypoxia (hypoxemia), leading to significant pathology, even mortality. Understanding transcriptome regulation of neonatal heart chambers in response to hypoxemia is necessary to develop chamber-specific therapies for infants with cyanotic congenital heart defects (CHDs). We sought to determine chamber-specific transcriptome programming during hypoxemic perinatal circulatory transition. We performed transcriptome-wide analysis on right ventricle (RV) and left ventricle (LV) of postnatal day 3 (P3) mouse hearts exposed to perinatal hypoxemia. Hypoxemia decreased baseline differences between RV and LV leading to significant attenuation of ventricular patterning (AVP), which involved several molecular pathways, including Wnt signaling suppression and cell cycle induction. Notably, robust changes in RV transcriptome in hypoxemic condition contributed significantly to the AVP. Remarkably, suppression of epithelial mesenchymal transition (EMT) and dysregulation of the TP53 signaling were prominent hallmarks of the AVP genes in neonatal mouse heart. Furthermore, members of the TP53-related gene family were dysregulated in the hypoxemic RVs of neonatal mouse and cyanotic Tetralogy of Fallot hearts. Integrated analysis of chamber-specific transcriptome revealed hypoxemia-specific changes that were more robust in RVs compared with LVs, leading to previously uncharacterized AVP induced by perinatal hypoxemia. Remarkably, reprogramming of EMT process and dysregulation of the TP53 network contributed to transcriptome remodeling of neonatal heart during hypoxemic circulatory transition. These insights may enhance our understanding of hypoxemia-induced pathogenesis in newborn infants with cyanotic CHD phenotypes. Key messages & During perinatal circulatory transition, transcriptome programming is a major driving force of cardiac chamber-specific maturation and adaptation to hemodynamic load and external environment. & During hypoxemic perinatal transition, transcriptome reprogramming may affect chamber-specific growth and development, particularly in newborns with congenital heart defects (CHDs). Yan Zhao and Xuedong Kang contributed equally to this work. The UCLA Congenital Heart
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