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Peer-reviewedCC BY 4.0The Febs Journal

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

  • Fadoua El Abdellaoui‐Soussi1,2,3
  • Apolonia Novillo4
  • Rocío Brea1
  • Marta Ysbert1
  • Lorena Cussó5,6,7
  • Gonzalo Pizarro‐Sánchez8,9,10
  • Manuel Desco5,6,7,11
  • Iván Hernández1
  • Ángel Luis Armesilla10,12,13
  • Ignacio Pérez de Castro1
  • Alicia R. Folgueras14,15
  • Juan Miguel Redondo2,10,16
1 more authors
  • Pablo Gómez‐del Arco1,2,10
16 affiliations
  1. 1Institute for Rare Diseases Research, Instituto de Salud Carlos III (ISCIII) Madrid Spain
  2. 2Gene Regulation in Cardiovascular Remodelling and Inflammation Laboratory Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid Spain
  3. 3Present address: Center for Stem Cells and Organoid Medicine (CuSTOM) Cincinnati Children's Hospital Medical Center Cincinnati OH USA
  4. 4Departamento de Biología Celular e Histología, Facultad de Medicina Universidad Complutense de Madrid (UCM) Spain
  5. 5Unidad de Imagen Avanzada Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid Spain
  6. 6Unidad de Medicina y Cirugía Experimental Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM) Madrid Spain
  7. 7CIBER de Salud Mental Instituto de Salud Carlos III Madrid Spain
  8. 8Cardiology Department, Ruber Juan Bravo Hospital and Faculty of Medicine, Health, and Sports Universidad Europea de Madrid Spain
  9. 9Translational Laboratory for Cardiovascular Imaging and Therapy Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) Madrid Spain
  10. 10Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) Madrid Spain
  11. 11Departamento de Bioingeniería Universidad Carlos III de Madrid Spain
  12. 12Facultad HM de Ciencias de la Salud Universidad Camilo José Cela Madrid Spain
  13. 13Instituto de Investigación Sanitaria HM Hospitales Madrid Spain
  14. 14Departamento de Bioquímica y Biología Molecular, Facultad de Medicina Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo Spain
  15. 15Instituto de Investigación Sanitaria del Principado de Asturias (ISPA) Oviedo Spain
  16. 16Cell‐Cell Communication & Inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBMSO) Consejo Superior de Investigaciones Científicas‐Universidad Autónoma de Madrid Spain
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{abdellaouisoussi2026chd4,
  title = {{Chd4 and ThPOK cooperate to preserve structural and electrophysiological integrity of the adult heart through Sprr1a repression}},
  author = {Fadoua El Abdellaoui‐Soussi and Apolonia Novillo and Rocío Brea and Marta Ysbert and Lorena Cussó and Gonzalo Pizarro‐Sánchez and Manuel Desco and Iván Hernández and Ángel Luis Armesilla and Ignacio Pérez de Castro and Alicia R. Folgueras and Juan Miguel Redondo and Pablo Gómez‐del Arco},
  journal = {The Febs Journal},
  year = {2026},
  month = may,
  doi = {10.1111/febs.70583},
  url = {https://doi.org/10.1111/febs.70583},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Chd4 and ThPOK cooperate to preserve structural and electrophysiological integrity of the adult heart through Sprr1a repression
AU  - Fadoua El Abdellaoui‐Soussi
AU  - Apolonia Novillo
AU  - Rocío Brea
AU  - Marta Ysbert
AU  - Lorena Cussó
AU  - Gonzalo Pizarro‐Sánchez
AU  - Manuel Desco
AU  - Iván Hernández
AU  - Ángel Luis Armesilla
AU  - Ignacio Pérez de Castro
AU  - Alicia R. Folgueras
AU  - Juan Miguel Redondo
AU  - Pablo Gómez‐del Arco
PY  - 2026
DA  - 2026/05/15
JO  - The Febs Journal
DO  - 10.1111/febs.70583
UR  - https://doi.org/10.1111/febs.70583
AB  - 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.
SN  - 1742-464X
SN  - 1742-4658
ER  -