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Gene-environment regulation of chamber-specific maturation during hypoxemic perinatal circulatory transition

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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).

  • Chamber-specific transcriptome changes during hypoxemic perinatal transition are yet to be fully elucidated.

  • Systems-based analysis of hypoxemic neonatal hearts at postnatal day 3 reveals chamber-specific transcriptome signatures during hypoxemic perinatal transition, which involve attenuation of ventricular patterning (AVP) and repression of epithelial mesenchymal transition (EMT).

  • Key regulatory circuits involved in hypoxemia response were identified including suppression of Wnt signaling, induction of cellular proliferation and dysregulation of TP53 network.

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Abbreviations

CHD:

Congenital heart defect

RVOT:

Right ventricle outflow tract

TOF:

Tetralogy of Fallot

EMT:

Epithelial mesenchymal transition

AVP:

Attenuation of ventricular patterning

CMC:

Cardiomyocyte

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Acknowledgments

We acknowledge the support from UCLA Clinical Genomics Center, Animal Physiology Core, and the Congenital Heart Defects—BioCore at UCLA.

Funding

This work was supported by grants from the American Heart Association Career Development Award (18CDA34110414), the Department of Defense-Congressionally Directed Medical Research Programs (W81XWH-18-1-0164), the NIH/NHLBI (1R56HL146738-01), and the UCLA David Geffen School of Medicine Research Innovation Seed Grant to M. Touma.

Author information

Author notes

  1. Yan Zhao and Xuedong Kang contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles 675 Charles E. Young Dr S, 3762 MacDonald Research Laboratories, Los Angeles, CA, 90024, USA

    Yan Zhao, Xuedong Kang, Alexander Barsegian, Jian He, Alejandra Guzman, Meena Garg, Nancy Halnon, Stanley F. Nelson & Marlin Touma

  2. Neonatal/Congenital Heart Laboratory, Cardiovascular Research Laboratory, University of California Los Angeles, Los Angeles, CA, USA

    Yan Zhao, Xuedong Kang, Alexander Barsegian, Jian He, Alejandra Guzman & Marlin Touma

  3. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Ryan P. Lau, Madhuri Wadhra, Fabiola Quintero-Rivera & Wayne W. Grody

  4. Department of Cardiothoracic Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Reshma Biniwale, Brian Reemtsen & Glen Van Arsdell

  5. Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Stanley F. Nelson

  6. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Stanley F. Nelson & Marlin Touma

  7. Children’s Discovery and Innovation Institute, Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Marlin Touma

  8. The Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA

    Marlin Touma

  9. Eli and Edythe Stem Cell Institute, University of California Los Angeles, Los Angeles, CA, USA

    Marlin Touma

  10. Institute of Precision Health, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Stanley F. Nelson & Marlin Touma

Authors
  1. Yan Zhao
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  2. Xuedong Kang
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Consortia

the UCLA Congenital Heart Defects BioCore Faculty

Contributions

MT conceived the project. MT, YZ, and XK designed and performed the research, analyzed most of the data, managed funding, and wrote the manuscript. AB, AJ, RB, GVA, NH, MG, and BR contributed to data acquisition and clinical insights. RPL and MW supported histology studies. FQR, WG, and SFN participated in manuscript review and editing.

Corresponding author

Correspondence to Marlin Touma.

Ethics declarations

All animal-related experimental protocols were approved by the UCLA Institutional Animal Care and Use Committee (IACUC). Therefore, all studies have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Conflict of interest

The authors declare that they have no conflict of interest.

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The UCLA Congenital Heart Defect BioCore Faculty: Marlin Touma, Nancy Halnon, Brian Reemtsen, Juan Alejos, Reshma Biniwale, Myke Federman, Leigh Reardon, Meena Garg, Amy Speirs, John P. Finn, Fabiola Quintero-Rivera, Wayne Grody, Glen Van Arsdell, and Stanley Nelson.

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Zhao, Y., Kang, X., Barsegian, A. et al. Gene-environment regulation of chamber-specific maturation during hypoxemic perinatal circulatory transition. J Mol Med 98, 1009–1020 (2020). https://doi.org/10.1007/s00109-020-01933-8

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