{ "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.", "abstract_shown": true, "affiliations": [ "Institute for Rare Diseases Research, Instituto de Salud Carlos III (ISCIII) Madrid Spain", "Gene Regulation in Cardiovascular Remodelling and Inflammation Laboratory Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid Spain", "Present address: Center for Stem Cells and Organoid Medicine (CuSTOM) Cincinnati Children's Hospital Medical Center Cincinnati OH USA", "Departamento de Biología Celular e Histología, Facultad de Medicina Universidad Complutense de Madrid (UCM) Spain", "Unidad de Imagen Avanzada Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid Spain", "Unidad de Medicina y Cirugía Experimental Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM) Madrid Spain", "CIBER de Salud Mental Instituto de Salud Carlos III Madrid Spain", "Cardiology Department, Ruber Juan Bravo Hospital and Faculty of Medicine, Health, and Sports Universidad Europea de Madrid Spain", "Translational Laboratory for Cardiovascular Imaging and Therapy Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) Madrid Spain", "Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) Madrid Spain", "Departamento de Bioingeniería Universidad Carlos III de Madrid Spain", "Facultad HM de Ciencias de la Salud Universidad Camilo José Cela Madrid Spain", "Instituto de Investigación Sanitaria HM Hospitales Madrid Spain", "Departamento de Bioquímica y Biología Molecular, Facultad de Medicina Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo Spain", "Instituto de Investigación Sanitaria del Principado de Asturias (ISPA) Oviedo Spain", "Cell‐Cell Communication & Inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBMSO) Consejo Superior de Investigaciones Científicas‐Universidad Autónoma de Madrid Spain" ], "article_type": "research article", "arxiv": null, "author_total": 13, "authors": [ { "affs": [ 0, 1, 2 ], "name": "Fadoua El Abdellaoui‐Soussi" }, { "affs": [ 3 ], "name": "Apolonia Novillo" }, { "affs": [ 0 ], "name": "Rocío Brea" }, { "affs": [ 0 ], "name": "Marta Ysbert" }, { "affs": [ 4, 5, 6 ], "name": "Lorena Cussó" }, { "affs": [ 7, 8, 9 ], "name": "Gonzalo Pizarro‐Sánchez" }, { "affs": [ 4, 5, 6, 10 ], "name": "Manuel Desco" }, { "affs": [ 0 ], "name": "Iván Hernández" }, { "affs": [ 9, 11, 12 ], "name": "Ángel Luis Armesilla" }, { "affs": [ 0 ], "name": "Ignacio Pérez de Castro", "orcid": "0000-0002-8822-8274" }, { "affs": [ 13, 14 ], "name": "Alicia R. Folgueras" }, { "affs": [ 1, 9, 15 ], "name": "Juan Miguel Redondo" }, { "affs": [ 0, 1, 9 ], "name": "Pablo Gómez‐del Arco", "orcid": "0000-0001-6748-7157" } ], "bibtex": "https://research.draconitic.com/paper/90sr6n6bfks5d.bib", "cited_by": 0, "doi": "10.1111/febs.70583", "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13731919/", "id": "90sr6n6bfks5d", "issns": [ "1742-464X", "1742-4658" ], "landing_url": "https://doi.org/10.1111/febs.70583", "language": "en", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Original Article" ], [ "openalex", "2705|Cardiac electrophysiology and arrhythmias" ] ], "openalex": "W7161289746", "pdf_url": null, "pmcid": "PMC13731919", "pmid": "42138467", "published": "2026-05-15", "publisher": null, "ris": "https://research.draconitic.com/paper/90sr6n6bfks5d.ris", "sources": [ { "first_seen": "2026-11-08T12:22:01Z", "native_id": "PMC13731919", "source": "pmc", "url": "https://doi.org/10.1111/febs.70583" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2705|Cardiac electrophysiology and arrhythmias", "subfield": "cardiovascular" } ], "title": "Chd4 and ThPOK cooperate to preserve structural and electrophysiological integrity of the adult heart through Sprr1a repression", "title_text": "Chd4 and ThPOK cooperate to preserve structural and electrophysiological integrity of the adult heart through Sprr1a repression", "type": "peer-reviewed", "updated_at": "2026-11-08T12:22:01Z", "url": "https://research.draconitic.com/paper/90sr6n6bfks5d", "venue": "The Febs Journal", "versions": [] }