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Gene-environment regulatory circuits of right ventricular pathology in tetralogy of fallot

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Abstract

The phenotypic spectrum of congenital heart defects (CHDs) is contributed by both genetic and environmental factors. Their interactions are profoundly heterogeneous but may operate on common pathways as in the case of hypoxia signaling during postnatal heart development in the context of CHDs. Tetralogy of Fallot (TOF) is the most common cyanotic (hypoxemic) CHD. However, how the hypoxic environment contributes to TOF pathogenesis after birth is poorly understood. We performed Genome-wide transcriptome analysis on right ventricle outflow tract (RVOT) specimens from cyanotic and noncyanotic TOF. Co-expression network analysis identified gene modules specifically associated with clinical diagnosis and hypoxemia status in the TOF hearts. In particular, hypoxia-dependent induction of myocyte proliferation is associated with E2F1-mediated cell cycle regulation and repression of the WNT11-RB1 axis. Genes enriched in epithelial mesenchymal transition (EMT), fibrosis, and sarcomere were also repressed in cyanotic TOF patients. Importantly, transcription factor analysis of the hypoxia-regulated modules suggested CREB1 as a putative regulator of hypoxia/WNT11-RB1 circuit. The study provides a high-resolution landscape of transcriptome programming associated with TOF phenotypes and unveiled hypoxia-induced regulatory circuit in cyanotic TOF. Hypoxia-induced cardiomyocyte proliferation involves negative modulation of CREB1 activity upstream of the WNT11-RB1 axis.

Key messages

  • Genetic and environmental factors contribute to congenital heart defects (CHDs).

  • How hypoxia contributes to Tetralogy of Fallot (TOF) pathogenesis after birth is unclear.

  • Systems biology-based analysis revealed distinct molecular signature in CHDs.

  • Gene expression modules specifically associated with cyanotic TOF were uncovered.

  • Key regulatory circuits induced by hypoxia in TOF pathogenesis after birth were unveiled.

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Abbreviations

CHD:

Congenital heart defect

RVOT:

Right ventricle outflow tract

TOF:

Tetralogy of Fallot

VSD:

Ventricular septal defect

EMT:

Epithelial mesenchymal transition

CMC:

Cardiomyocyte

RPKM:

Reads per kilo base per million of mapped reads

PCA:

Principal component analysis

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Acknowledgments

We acknowledge Dr. Yibin Wang for the critical review of this manuscript. We acknowledge the support of the NINDS Informatics Center, the Clinical Genomics Center, the Animal Physiology Core, and the Congenital Heart Defects-BioCore at UCLA.

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, Stanley Nelson, Yibin Wang.

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. We acknowledge the support of the National Institute of Neurological Disorders and Stroke NINDS [P30 NS062691] to G. Coppola and F. Gao.

Author information

Author notes

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

Authors and Affiliations

  1. Department of Pediatrics, David Geffen School of Medicine, University of California, 10833 Le Conte Ave, MDCC-B2-375, Los Angeles, CA, 90095, USA

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

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

    Yan Zhao, Xuedong Kang & Marlin Touma

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

    Fuying Gao, Giovanni Coppola & Stanley F. Nelson

  4. Department of Pathology and Laboratory Medicine, Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Ryan P. Lau, Madhuri Wadehra & Fabiola Quintero-Rivera

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

    Reshma Biniwale, Brian Reemtsen & Glen Van Arsdell

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

    Stanley F. Nelson & Marlin Touma

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

    Stanley F. Nelson & Marlin Touma

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

    Marlin Touma

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

    Marlin Touma

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

    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

  • 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
  • , Stanley Nelson
  •  & Yibin Wang

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. FG and GC supported bioinformatics analysis. RB, GVA, NH, MG, and BR contributed human specimens and provided clinical insights. RPL and MW supported histology studies. FQR and SFN supported genetics studies and participated in manuscript review and editing.

Corresponding author

Correspondence to Marlin Touma.

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Ethical standard

All human studies were conducted in accordance with regulation of the University of California Los Angeles Institutional Review Board (UCLA IRB). 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. Informed consents were obtained from parents/legally authorized representative of participants (minors) or next of kin (for the deceased donors).

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The authors declare that they have no conflict of interest.

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Zhao, Y., Kang, X., Gao, F. et al. Gene-environment regulatory circuits of right ventricular pathology in tetralogy of fallot. J Mol Med 97, 1711–1722 (2019). https://doi.org/10.1007/s00109-019-01857-y

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  • DOI: https://doi.org/10.1007/s00109-019-01857-y

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