Language
English
Publication Date
12-5-2025
Journal
Nature Communications
DOI
10.1038/s41467-025-66959-3
PMID
41350282
PMCID
PMC12712101
PubMedCentral® Posted Date
12-5-2025
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Animals, Homeobox Protein PITX2, Homeodomain Proteins, Transcription Factors, Sinoatrial Node, Myocytes, Cardiac, Mice, Humans, Induced Pluripotent Stem Cells, Atrial Fibrillation, Sick Sinus Syndrome, Arrhythmias, Cardiac, Gene Dosage, Female, Gene Expression Regulation, Developmental, Arrhythmias, Morphogenesis, Transcriptomics
Published Open-Access
yes
Recommended Citation
van der Maarel, Lieve E; Mungroo, M Ridwane; Mulleners, Otto J; et al., "PITX2 Dosage-Dependent Changes in Pacemaker Cell State Underlie Sinus Node Dysfunction and Atrial Arrhythmias" (2025). Faculty, Staff and Students Publications. 6401.
https://digitalcommons.library.tmc.edu/baylor_docs/6401