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

Yan Zhao; Xuedong Kang; Fuying Gao; Alejandra Guzman; Ryan P Lau; Reshma Biniwale; Madhuri Wadehra; Brian Reemtsen; Meena Garg; Nancy Halnon; Fabiola Quintero-Rivera; Glen Van Arsdell; Giovanni Coppola; Stanley F Nelson; Marlin Touma; UCLA Congenital Heart Defects BioCore Faculty

doi:10.1007/s00109-019-01857-y

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

J Mol Med (Berl). 2019 Dec;97(12):1711-1722. doi: 10.1007/s00109-019-01857-y. Epub 2019 Dec 13.

Authors

Yan Zhao^{1

2}, Xuedong Kang^{1

2}, Fuying Gao³, Alejandra Guzman¹, Ryan P Lau⁴, Reshma Biniwale⁵, Madhuri Wadehra⁴, Brian Reemtsen⁵, Meena Garg¹, Nancy Halnon¹, Fabiola Quintero-Rivera⁴, Glen Van Arsdell⁵, Giovanni Coppola³, Stanley F Nelson^{1

3

6

7}, Marlin Touma^{8

9

10

11

12

13

14}; UCLA Congenital Heart Defects BioCore Faculty

Collaborators

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

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.
² Neonatal/Congenital Heart Laboratory, Cardiovascular Research Laboratory, University of California, Los Angeles, CA, USA.
³ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁴ Department of Pathology and Laboratory Medicine, Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁵ Department of Cardiothoracic Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁶ Department of Human Genetics, Institute of Precision Health, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁷ Institute of Precision Health, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁸ Department of Pediatrics, David Geffen School of Medicine, University of California, 10833 Le Conte Ave, MDCC-B2-375, Los Angeles, CA, 90095, USA. mtouma@mednet.ucla.edu.
⁹ Neonatal/Congenital Heart Laboratory, Cardiovascular Research Laboratory, University of California, Los Angeles, CA, USA. mtouma@mednet.ucla.edu.
¹⁰ Department of Human Genetics, Institute of Precision Health, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. mtouma@mednet.ucla.edu.
¹¹ Institute of Precision Health, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. mtouma@mednet.ucla.edu.
¹² Department of Pediatrics, Children's Discovery and Innovation Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. mtouma@mednet.ucla.edu.
¹³ The Molecular Biology Institute, University of California, Los Angeles, CA, USA. mtouma@mednet.ucla.edu.
¹⁴ Eli and Edythe Stem Cell Institute, University of California, Los Angeles, CA, USA. mtouma@mednet.ucla.edu.

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.

Keywords: Congenital heart defects; Genome; Hypoxia; Tetralogy of Fallot; Transcriptome.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Child
Child, Preschool
Cohort Studies
Cyclic AMP Response Element-Binding Protein / metabolism
E2F1 Transcription Factor / metabolism
Epithelial-Mesenchymal Transition / genetics
Female
Gene Expression Profiling
Gene Expression Regulation / genetics
Gene Regulatory Networks / genetics
Genome
Heart Ventricles / metabolism*
Heart Ventricles / pathology
Humans
Hypoxia / metabolism*
Infant
Male
Signal Transduction / genetics
Tetralogy of Fallot / genetics
Tetralogy of Fallot / metabolism*
Transcriptome / genetics*
Transcriptome / physiology
Wnt Proteins / metabolism

Substances

CREB1 protein, human
Cyclic AMP Response Element-Binding Protein
E2F1 Transcription Factor
E2F1 protein, human
Wnt Proteins
Wnt11 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding