Chd4 and ThPOK cooperate to preserve structural and electrophysiological integrity of the adult heart through Sprr1a repression.

The structural and electrophysiological stability of the adult heart depends on coordinated transcriptional repression governed by chromatin remodeling and nuclear architecture. The Chd4/NuRD complex is essential to maintain cardiomyocyte identity, and its deletion leads to arrhythmias, aberrant expression of skeletal muscle sarcomeric genes, and dysregulation of key components of the cardiac conduction system, including Hcn4, Cntn2, and Cx40. However, while the mechanisms by which Chd4 cooperates with additional transcriptional regulators to preserve adult cardiac homeostasis remain poorly understood, previous studies have identified ThPOK, a lamina-associated transcription factor, as a candidate Chd4 partner in cardiomyocytes. Using cardiomyocyte-specific conditional mouse models, we show that combined loss of Chd4 and ThPOK markedly exacerbates conduction defects, leading to more severe arrhythmias and accelerated sudden cardiac death compared with Chd4 loss alone. Transcriptomic profiling revealed a synergistic upregulation of Sprr1a, a protein normally expressed in the epidermis where it contributes to keratinocyte differentiation and cornification. Sprr1a induction correlated with downregulation of the cardioprotective microRNA miR-150-5p, a change driven by Chd4 deletion; however, miR-150-5p levels were not further reduced in double-knockout hearts, indicating that ThPOK contributes to Sprr1a de-repression through a distinct mechanism. Notably, Sprr1a upregulation was also observed in Lmna mutant hearts, suggesting a link between its de-repression and cardiac-specific nuclear lamina dysfunction. Together, these findings uncover a cooperative Chd4;ThPOK regulatory axis that preserves transcriptional integrity and safeguards structural and electrical homeostasis in the adult murine heart.