PITX2 dosage-dependent changes in pacemaker cell state underlie sinus node dysfunction and atrial arrhythmias

Nature Communications, vol. 16, pp. 11197

Abstract

Physiologically relevant increases in transcription factor dosage and their role in development and disease remain largely unexplored. Genomic deletions upstream of the Paired-like homeodomain transcription factor gene (PITX2), identified in patients with sinus node dysfunction and atrial fibrillation and modeled in mice (delB), rewire the local epigenetic landscape, increasing PITX2 expression. Here, we demonstrate that pacemaker cardiomyocytes in the embryonic delB sinus node ectopically express PITX2 at physiological dosages in a heterogeneous pattern. The prenatal delB sinus node forms discrete subdomains showing PITX2 dosage-dependent mild or severe loss of pacemaker cardiomyocyte identity. Respective subdomain sizes and severity of sinus node dysfunction and atrial arrhythmia susceptibility align with PITX2 dosage. Ectopic PITX2c expression in human induced pluripotent stem cell-derived pacemaker cardiomyocytes causes PITX2 dosage-dependent transcriptional and electrophysiological changes paralleling those in delB mice. Our findings provide a mechanistic link between genetic variation-driven ectopic PITX2 expression, sinus node dysfunction and atrial arrhythmogenesis, illustrating how spatiotemporally defined increases in transcription factor dosage can translate into developmental defects and disease predisposition.

Authors 17

1. Lieve E. van der Maarel

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

2. Mohammad Ridwane Mungroo

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

3. Otto J. Mulleners

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

4. Mathilde R. Rivaud Aachen Laboratory of Experimental Cardiology

   Leiden University Medical Center · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

   Laboratory of Experimental Cardiology, Leiden University Medical Center, Leiden, the Netherlands

5. Arie O. Verkerk

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Department of Clinical Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

   Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

6. Karel van Duijvenboden

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

7. Freek H. T. Tiel Groenestege

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

8. Jeffrey D. Steimle

   Baylor College of Medicine

   Affiliation as printed

   Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA

9. Lianne Fokkert

   Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

   Affiliation as printed

   Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

10. Corrie de Gier-de Vries

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

    Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

11. Mischa Klerk

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

    Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

12. Arnie Boender

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

    Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

13. James F. Martin

    Baylor College of Medicine

    Affiliation as printed

    Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA

14. Bjarke Jensen

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

    Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

15. Gerard J.J. Boink

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

    Department of Clinical Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

    Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

    PacingCure BV, Amsterdam, the Netherlands

16. Harsha D. Devalla

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

    Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

17. Vincent M. Christoffels corresponding

    Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

    Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands. v.m.christoffels@amsterdamumc.nl

    Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands