Gene Expression Networks in the Murine Pulmonary Myocardium Provide Insight into the Pathobiology of Atrial Fibrillation

The pulmonary myocardium is a muscular coat surrounding the pulmonary and caval veins. Although its definitive physiological function is unknown, it may have a pathological role as the source of ectopic beats initiating atrial fibrillation. How the pulmonary myocardium gains pacemaker function is not clearly defined, although recent evidence indicates that changed transcriptional gene expression networks are at fault. The gene expression profile of this distinct cell type in situ was examined to investigate underlying molecular events that might contribute to atrial fibrillation. Via systems genetics, a whole-lung transcriptome data set from the BXD recombinant inbred mouse resource was analyzed, uncovering a pulmonary cardiomyocyte gene network of 24 transcripts, coordinately regulated by chromosome 1 and 2 loci. Promoter enrichment analysis and interrogation of publicly available ChIP-seq data suggested that transcription of this gene network may be regulated by the concerted activity of NKX2-5, serum response factor, myocyte enhancer factor 2, and also, at a post-transcriptional level, by RNA binding protein motif 20. Gene ontology terms indicate that this gene network overlaps with molecular markers of the stressed heart. Therefore, we propose that perturbed regulation of this gene network might lead to altered calcium handling, myocyte growth, and contractile force contributing to the aberrant electrophysiological properties observed in atrial fibrillation. We reveal novel molecular interactions and pathways representing possible therapeutic targets for atrial fibrillation. In addition, we highlight the utility of recombinant inbred mouse resources in detecting and characterizing gene expression networks of relatively small populations of cells that have a pathological significance.

• Publication year

  2017

• Venue

  G3: Genes, Genomes, Genetics

• Publication date

  2017-07-18

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1534/g3.117.044651PMID 28720711PMCID 5592927
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

  2017cited by this paper
• Phospholamban and sarcolipin: Are they functionally redundant or distinct regulators of the Sarco(Endo)Plasmic Reticulum Calcium ATPase?

  2016influential reference
• Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy

  2016cited by this paper
• Modeling structural and functional deficiencies of RBM20 familial dilated cardiomyopathy using human induced pluripotent stem cells.

  2016cited by this paper
• Left Atrial Transcriptional Changes Associated With Atrial Fibrillation Susceptibility and Persistence

  2015influential reference
• Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

  2015influential reference
• A novel human R25C-phospholamban mutation is associated with super-inhibition of calcium cycling and ventricular arrhythmia.

  2015cited by this paper
• Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of the Triadin Knockout Syndrome

  2015cited by this paper
• ADP-stimulated contraction: A predictor of thin-filament activation in cardiac disease

  2015influential reference
• SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia

  2015cited by this paper
• A common Shox2–Nkx2-5 antagonistic mechanism primes the pacemaker cell fate in the pulmonary vein myocardium and sinoatrial node

  2015influential reference
• Sequential Binding of MEIS1 and NKX2-5 on the Popdc2 Gene: A Mechanism for Spatiotemporal Regulation of Enhancers during Cardiogenesis

  2015influential reference
• Systems Genetics of Liver Fibrosis: Identification of Fibrogenic and Expression Quantitative Trait Loci in the BXD Murine Reference Population

  2014cited by this paper
• Rapid Identification of Major-Effect Genes Using the Collaborative Cross

  2014cited by this paper
• A novel PITX2c loss-of-function mutation associated with familial atrial fibrillation.

  2014cited by this paper
• Interactive visualization and analysis of large-scale sequencing datasets using ZENBU

  2014cited by this paper
• Worldwide Epidemiology of Atrial Fibrillation: A Global Burden of Disease 2010 Study

  2014cited by this paper
• GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development

  2014cited by this paper
• Identification of the cis-element and bZIP DNA binding motifs for the autogenous negative control of mouse NOSTRIN.

  2014cited by this paper
• A Kir3.4 mutation causes Andersen–Tawil syndrome by an inhibitory effect on Kir2.1

  2014cited by this paper
• A promoter-level mammalian expression atlas

  2014influential reference
• Rbm20-deficient cardiogenesis reveals early disruption of RNA processing and sarcomere remodeling establishing a developmental etiology for dilated cardiomyopathy.

  2014influential reference
• Corin in Natriuretic Peptide Processing and Hypertension

  2014cited by this paper
• PITX2C loss-of-function mutations responsible for idiopathic atrial fibrillation

  2014cited by this paper
• A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation.

  2013cited by this paper
• Zinc Finger Protein 451 Is a Novel Smad Corepressor in Transforming Growth Factor-β Signaling*

  2013cited by this paper
• Triadin regulates cardiac muscle couplon structure and microdomain Ca(2+) signalling: a path towards ventricular arrhythmias.

  2013cited by this paper
• WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013

  2013influential reference
• Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation

  2013influential reference
• FGF12 is a candidate Brugada syndrome locus.

  2013influential reference
• The F‐BAR protein NOSTRIN participates in FGF signal transduction and vascular development

  2012cited by this paper
• Calcium Leak Through Ryanodine Receptors Leads to Atrial Fibrillation in 3 Mouse Models of Catecholaminergic Polymorphic Ventricular Tachycardia

  2012cited by this paper
• Myosin Light Chain Phosphorylation Is Critical for Adaptation to Cardiac Stress

  2012influential reference
• RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing

  2012influential reference
• Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human

  2012cited by this paper
• Sublocalization of Rab23, a mediator of Sonic hedgehog signaling pathway, in hepatocellular carcinoma cell lines.

  2012cited by this paper
• FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise.

  2012cited by this paper
• LRP2 is an auxiliary SHH receptor required to condition the forebrain ventral midline for inductive signals.

  2012cited by this paper
• TBX5 drives Scn5a expression to regulate cardiac conduction system function.

  2012cited by this paper
• Discontinuous thoracic venous cardiomyocytes and heart exhibit synchronized developmental switch of troponin isoforms

  2012cited by this paper
• oPOSSUM-3: Advanced Analysis of Regulatory Motif Over-Representation Across Genes or ChIP-Seq Datasets

  2012influential reference
• Novel GATA6 loss-of-function mutation responsible for familial atrial fibrillation.

  2012cited by this paper
• Expression QTL mapping in regulatory and helper T cells from the BXD family of strains reveals novel cell-specific genes, gene-gene interactions and candidate genes for auto-immune disease

  2011influential reference
• Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart

  2011influential reference
• Mechanisms of T-box gene function in the developing heart.

  2011cited by this paper
• Transforming growth factor (TGF)-β signaling in cardiac remodeling.

  2011cited by this paper
• Decreased sarcolipin protein expression and enhanced sarco(endo)plasmic reticulum Ca2+ uptake in human atrial fibrillation.

  2011cited by this paper
• The collaborative cross: a recombinant inbred mouse population for the systems genetic era.

  2011cited by this paper
• Cardiac Myosin Light Chain Kinase Is Necessary for Myosin Regulatory Light Chain Phosphorylation and Cardiac Performance in Vivo*

  2010cited by this paper
• Genetic basis of hypertrophic cardiomyopathy

  2010cited by this paper
• GeneCards Version 3: the human gene integrator

  2010influential reference
• Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart

  2010cited by this paper
• Cardiac conduction is required to preserve cardiac chamber morphology

  2010cited by this paper
• Genetic Variation in the Inwardly Rectifying K+ Channel Subunits KCNJ3 (GIRK1) and KCNJ5 (GIRK4) in Patients with Sinus Node Dysfunction

  2010influential reference
• Gene expression in the mouse eye: an online resource for genetics using 103 strains of mice

  2009influential reference
• Detection and interpretation of expression quantitative trait loci (eQTL).

  2009cited by this paper
• Cx30.2 enhancer analysis identifies Gata4 as a novel regulator of atrioventricular delay

  2009cited by this paper
• NOSTRINβ– A Shortened NOSTRIN Variant with A Role in Transcriptional Regulation

  2009influential reference
• ZNF451 is a novel PML body- and SUMO-associated transcriptional coregulator.

  2008cited by this paper
• Of rodents and humans: a light microscopic and ultrastructural study on cardiomyocytes in pulmonary veins

  2008influential reference
• The enigmatic role of the ankyrin repeat domain 1 gene in heart development and disease.

  2008cited by this paper
• The COOH terminus of megalin regulates gene expression in opossum kidney proximal tubule cells.

  2008cited by this paper
• Moving toward a system genetics view of disease

  2007cited by this paper
• Synthetic Reconstruction of Zoonotic and Early Human Severe Acute Respiratory Syndrome Coronavirus Isolates That Produce Fatal Disease in Aged Mice

  2007cited by this paper
• Pitx2c and Nkx2-5 Are Required for the Formation and Identity of the Pulmonary Myocardium

  2007influential reference
• Myozenin 2 Is a Novel Gene for Human Hypertrophic Cardiomyopathy

  2007cited by this paper
• Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction.

  2007influential reference
• Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia.

  2007cited by this paper
• Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin.

  2006cited by this paper
• Myocardial sleeves of pulmonary veins and atrial fibrillation: a postmortem histopathological study of 100 subjects

  2006cited by this paper
• Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis.

  2006influential reference
• Mouse disabled 2 interacting protein 2 functions as a transcriptional repressor through direct binding onto its own promoter.

  2005influential reference
• Specific pattern of ionic channel gene expression associated with pacemaker activity in the mouse heart

  2005cited by this paper
• Mutations in the genes KCND2 and KCND3 encoding the ion channels Kv4.2 and Kv4.3, conducting the cardiac fast transient outward current (ITO,f), are not a frequent cause of long QT syndrome.

  2005cited by this paper
• Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function

  2005influential reference
• The Junction Between the Left Atriuni and the Pulmonary Veins An Anatomic Study of Human Hearts

  2005cited by this paper
• The SRF target gene Fhl2 antagonizes RhoA/MAL-dependent activation of SRF.

  2004influential reference
• WebQTL: rapid exploratory analysis of gene expression and genetic networks for brain and behavior

  2004influential reference
• Morphology of Atrial Myocardial Extensions Into Human Caval Veins: A Postmortem Study in Patients With and Without Atrial Fibrillation

  2004cited by this paper
• The sensitive giant: the role of titin-based stretch sensing complexes in the heart.

  2004cited by this paper
• Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF-β1

  2004cited by this paper
• The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system

  2004cited by this paper
• A new set of BXD recombinant inbred lines from advanced intercross populations in mice

  2004cited by this paper
• The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules.

  2003cited by this paper
• Structure of the core domain of human cardiac troponin in the Ca2+-saturated form

  2003influential reference
• Nitric Oxide and Cardiac Function: Ten Years After, and Continuing

  2003cited by this paper
• Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death

  2003cited by this paper
• Identification of three novel OA1 gene mutations identified in three families misdiagnosed with congenital nystagmus and carrier status determination by real-time quantitative PCR assay

  2003cited by this paper
• Myosin light chain isoforms modify force-generating ability of cardiac myosin by changing the kinetics of actin-myosin interaction.

  2003influential reference
• Anatomic Characteristics of Extensions of Atrial Myocardium into the Pulmonary Veins in Subjects With and Without Atrial Fibrillation

  2003cited by this paper
• Morphology of atrial myocardium in human pulmonary veins: a postmortem analysis in patients with and without atrial fibrillation.

  2003cited by this paper
• WebQTL - Web-based complex trait analysis

  2003cited by this paper
• NOSTRIN: A protein modulating nitric oxide release and subcellular distribution of endothelial nitric oxide synthase

  2002influential reference
• COUP-TF1 Antagonizes Nkx2.5-mediated Activation of the Calreticulin Gene during Cardiac Development*

  2001influential reference
• Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes

  2001cited by this paper
• Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation

  2001influential reference
• Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles.

  2001influential reference
• Differential expression of cardiac titin isoforms and modulation of cellular stiffness.

  2000cited by this paper
• Cardiac and smooth muscle cell contribution to the formation of the murine pulmonary veins

  2000influential reference
• Left Atrial Myocardial Extension onto Pulmonary Veins in Humans:

  2000cited by this paper

• Integrated Genomic Approaches to Elucidate the Genetic Basis of Brugada Syndrome in Taiwanese Patients

  2025cites this paper
• Decoding the PITX2-controlled genetic network in atrial fibrillation

  2022cites this paper
• Nintedanib induces gene expression changes in the lung of induced-rheumatoid arthritis–associated interstitial lung disease mice

  2022cites this paper
• α1-adrenergic receptors accompanied by GATA4 expression are related to proarrhythmic conduction and automaticity in rat interatrial septum

  2022cites this paper
• Time series of transcriptome analysis in entire lung development stages provide insights into the origin of NO2 related lung diseases.

  2022cites this paper
• 51 Regional and TBX5- Dependent Gene Expression in the Atria: Implications for Pulmonary Vein Development and Atrial Fibrillation

  2020cites this paper
• Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension

  2020cites this paper
• Regional and TBX5-Dependent Gene Expression in the Atria: Implications for Pulmonary Vein Development and Atrial Fibrillation

  2020cites this paper
• Attenuation of inward rectifier potassium current contributes to the α1‐adrenergic receptor‐induced proarrhythmicity in the caval vein myocardium

  2020cites this paper
• Genetics Of Atrial Fibrilation: In Search Of Novel Therapeutic Targets.

  2019cites this paper
• The local repolarization heterogeneity in the murine pulmonary veins myocardium contributes to the spatial distribution of the adrenergically induced ectopic foci

  2019cites this paper