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

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月5日

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  • Lieve E. van der Maarel,
  • M. Ridwane Mungroo,
  • Otto J. Mulleners,
  • Mathilde R. Rivaud,
  • Arie O. Verkerk,
  • Karel van Duijvenboden,
  • Freek H. T. Tiel Groenestege,
  • Jeffrey D. Steimle,
  • Lianne Fokkert,
  • Corrie de Gier-de Vries,
  • Mischa Klerk,
  • Arie. R. Boender,
  • James F. Martin,
  • Bjarke Jensen,
  • Gerard J. J. Boink,
  • Harsha D. Devalla,
  • Vincent M. Christoffels

摘要

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.