ArticleCell stem cell2021
Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes.
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Article in Cell stem cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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84citing papers in PubMed
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Who cites it
84 citing papers in PubMed, 136 citations in OpenAlex.
- A highly penetrantbioRxiv : the preprint server for biology · 2026Article
- The cardiac 4D nucleome: nuclear and chromatin dynamics across development, disease and ageing.Nature reviews. Cardiology · 2026Review
- Antibody-trapping presents a widespread pitfall for microscopy and genomics in the nucleus.Nucleic acids research · 2026Article
- Transcription and cohesin direct domain boundary spatial positioning and are linked to Friedreich's ataxia.Molecular cell · 2026Article
- Review
- The cytoskeleton contributes to abnormal genome-lamina interactions in LMNA-deficient cardiomyocytes.The Journal of cell biology · 2026Article
- RNA-Based Therapies for Treating Monogenic Cardiomyopathies.The Canadian journal of cardiology · 2026Review
- Emerging Mechanisms and Therapeutic Strategies in Dilated Cardiomyopathy.Biomedicines · 2026Review
- Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming.Nature metabolism · 2026Article
- High-Throughput Methods for Variant Functional Assessment in Cardiac Disease.Circulation. Genomic and precision medicine · 2026Review
- A Mechano-Feedback Loop Orchestrated by SUN1/2 Governs Cellular Mechanoadaptation via Lamina-Associated Domain Remodeling.Research (Washington, D.C.) · 2026Article
- Genetic loci responsible for atrioventricular block in children.Frontiers in cell and developmental biology · 2026Review
- Epigenetic Regulation in Dilated Cardiomyopathy.Heart failure clinics · 2026Review
- Perinuclear organelle trauma at the nexus of cardiomyopathy pathogenesis arising from loss of functionNucleus (Austin, Tex.) · 2025Review
- Reorganization of H3K9me2-modified chromatin regions during mouse embryonic development.Developmental biology · 2025Article
- Cardiomyocyte Nuclear Pleomorphism in a Mouse Model of Inherited Hypertrophic Cardiomyopathy.Journal of cardiovascular development and disease · 2025Article
- LMNA-related cardiomyopathy: From molecular pathology to cardiac gene therapy.Journal of advanced research · 2025Review
- Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Local Non-Coding Regulatory Elements in Muscular Dystrophies.International journal of molecular sciences · 2025Review
- Smartwatch bradycardia alarms leading to a diagnosis of lamin A/C cardiomyopathy: a case report.European heart journal. Case reports · 2025Article
24 more citing papers are in PubMed but not listed here.
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Authors and funding
24 authors at 5 institutions in 1 country.
Parisha P ShahDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Wenjian LvDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Joshua H RhoadesDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Institute for Biomedical Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Andrey PoleshkoDepartment of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Deepti AbbeyPenn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Matthew A CaporizzoPenn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Physiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Pennsylvania Muscle Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Ricardo Linares-SaldanaDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Julie G HefflerPenn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Physiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Pennsylvania Muscle Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Nazish SayedStanford Cardiovascular Institute, Department of Surgery, Division of Vascular Surgery, Stanford University, Stanford, CA 94305, USA.
Dilip ThomasStanford Cardiovascular Institute, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Qiaohong WangDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Liam J StantonDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Kenneth BediDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Michael P MorleyDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Lung Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Thomas P CappolaDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Anjali T OwensDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Kenneth B MarguliesDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
David B FrankPenn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Joseph C WuStanford Cardiovascular Institute, Department of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
Daniel J RaderPenn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Wenli YangDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Institute for Regenerative Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Benjamin L ProsserPenn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Physiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Pennsylvania Muscle Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA.
Kiran MusunuruDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA. Electronic address: kiranmusunuru@gmail.com.
Rajan JainDepartment of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Penn Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA; Institute for Regenerative Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19014, USA. Electronic address: jainr@pennmedicine.upenn.edu.
University of Pennsylvania · USCalifornia Institute for Regenerative Medicine · USCardiovascular Institute of the South · USLung Institute · USStanford University · US
Funding
Human iPSCs for Elucidating Intercellular Crosstalk Signaling in Dilated CardiomyopathyR01HL141371 · NHLBI · STANFORD UNIVERSITY · PI WONG, WING H., WU, JOSEPH C. · 2018 to 2025
$6.2MDiagnosis, Prevention, And Treatment Of Cardiovascular Diseases With Genome EditingR35HL145203 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI MUSUNURU, KIRAN · 2019 to 2025
$5.7MDecoding the bridges and barriers to cellular reprogramming and lineage identityR01GM137425 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI JAIN, RAJAN, RAJ, ARJUN · 2019 to 2023
$5.6MMTSS1 in Myocardial DiseaseR01HL141232 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI THOMAS P. CAPPOLA, Scott Michael Damrauer · 2019 to 2026
$4.7MMechanical Stress-Dependent Remodeling of the Cardiac Microtubule NetworkR01HL149891 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI Kenneth Ber Margulies, Benjamin Lears Prosser · 2020 to 2026
$4.2MDeciphering Nuclear Lamina-Chromatin Organization in Cellular Competence and Cardiac DevelopmentDP2HL147123 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI JAIN, RAJAN · 2018 to 2018
$2.4MWnt-mediated epithelial-endothelial crosstalk in the generation and regeneration of the lung alveolusK08HL140129 · NHLBI · CHILDREN'S HOSP OF PHILADELPHIA · PI FRANK, DAVID BRIAN · 2018 to 2022
$797kDefining the role of HOPX and genome-nuclear lamina interactions in cardiomyocyte commitmentF31HL147416 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI LINARES SALDANA, RICARDO · 2019 to 2021
$111kNHLBI NIH HHS DP2 HL147123NHLBI NIH HHS F31 HL147416NHLBI NIH HHS K08 HL140129NHLBI NIH HHS R01 HL141232NHLBI NIH HHS R01 HL141371NHLBI NIH HHS R01 HL149891NHLBI NIH HHS R35 HL145203NIGMS NIH HHS R01 GM137425
Abstract
Pathogenic mutations in LAMIN A/C (LMNA) cause abnormal nuclear structure and laminopathies. These diseases have myriad tissue-specific phenotypes, including dilated cardiomyopathy (DCM), but how LMNA mutations result in tissue-restricted disease phenotypes remains unclear. We introduced LMNA mutations from individuals with DCM into human induced pluripotent stem cells (hiPSCs) and found that hiPSC-derived cardiomyocytes, in contrast to hepatocytes or adipocytes, exhibit aberrant nuclear morphology and specific disruptions in peripheral chromatin. Disrupted regions were enriched for transcriptionally active genes and regions with lower LAMIN B1 contact frequency. The lamina-chromatin interactions disrupted in mutant cardiomyocytes were enriched for genes associated with non-myocyte lineages and correlated with higher expression of those genes. Myocardium from individuals with LMNA variants similarly showed aberrant expression of non-myocyte pathways. We propose that the lamina network safeguards cellular identity and that pathogenic LMNA variants disrupt peripheral chromatin with specific epigenetic and molecular characteristics, causing misexpression of genes normally expressed in other cell types.
Indexed as
Cardiomyopathy, DilatedInduced Pluripotent Stem CellsChromatinHumansLamin Type AMutationMyocytes, CardiacChromatinLamin Type ALMNA protein, humangenome organizationhiPSClaminopathyperipheral heterochromatin
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