PITX2 dosage-dependent changes in pacemaker cell state underlie sinus node dysfunction and atrial arrhythmias
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
- Jeffrey D. Steimle (ORCID: https://orcid.org/0000-0002-1369-9661)
- Arnie Boender (ORCID: https://orcid.org/0009-0003-3709-9729)
- Gerard J.J. Boink (ORCID: https://orcid.org/0000-0002-6592-5106)
- Karel van Duijvenboden (ORCID: https://orcid.org/0000-0001-5691-8097)
- Vincent M. Christoffels (ORCID: https://orcid.org/0000-0003-4131-2636)
- Bjarke Jensen (ORCID: https://orcid.org/0000-0002-7750-8035)
- Mathilde R. Rivaud (ORCID: https://orcid.org/0000-0002-0680-3483)
- Corrie de Gier-de Vries (ORCID: https://orcid.org/0000-0001-6272-5961)
- Harsha D. Devalla (ORCID: https://orcid.org/0000-0001-5343-1021)
- Mohammad Ridwane Mungroo (ORCID: https://orcid.org/0000-0002-8056-4011)
- Lianne Fokkert
- Arie O. Verkerk (ORCID: https://orcid.org/0000-0003-2140-834X)
- Mischa Klerk (ORCID: https://orcid.org/0000-0002-3725-9943)
- Lieve E. van der Maarel (ORCID: https://orcid.org/0000-0001-6686-4029)
- James F. Martin (ORCID: https://orcid.org/0000-0002-7842-9857)
- Otto J. Mulleners (ORCID: https://orcid.org/0009-0000-6205-9591)
- Freek H. T. Tiel Groenestege
Institutions
- Baylor College of Medicine (US)
- Leiden University Medical Center (NL)
- MRC Holland (Netherlands) (NL)
- Amsterdam University Medical Centers (NL)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-05
- DOI
- https://doi.org/10.1038/s41467-025-66959-3
- Citations
- 2
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Dutch Cardiovascular Alliance
- Vivian L. Smith Foundation
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Institutes of Health
- Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers
- Amsterdams Universiteitsfonds
- National Heart, Lung, and Blood Institute
- HORIZON EUROPE European Innovation Council