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Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes
Parisha P Shah1, Wenjian Lv2, Joshua H Rhoades3
1Department 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.
Insights
Pathogenic mutations in Lamin A/C (LMNA) cause abnormal nuclear structure. In heart cells, these mutations disrupt chromatin, leading to misexpression of genes from other cell types, explaining tissue-specific diseases like dilated cardiomyopathy.
Area of Science:
- Cell Biology
- Genetics
- Molecular Biology
Background:
- Pathogenic mutations in Lamin A/C (LMNA) are linked to laminopathies, a group of diseases with diverse tissue-specific phenotypes.
- The precise mechanisms by which LMNA mutations lead to tissue-restricted disease manifestations, such as dilated cardiomyopathy (DCM), are not fully understood.
Purpose of the Study:
- To investigate how LMNA mutations cause distinct cellular defects and tissue-specific phenotypes in laminopathies.
- To explore the role of lamina-chromatin interactions in maintaining cellular identity and preventing disease.
Main Methods:
- Utilized human induced pluripotent stem cells (hiPSCs) derived from individuals with LMNA mutations causing DCM.
- Compared nuclear morphology and peripheral chromatin organization in hiPSC-derived cardiomyocytes, hepatocytes, and adipocytes.
- Analyzed transcriptionally active genes and LAMIN B1 contact frequency in disrupted chromatin regions.
- Examined gene expression patterns in mutant cardiomyocytes and human myocardium samples.
Main Results:
- hiPSC-derived cardiomyocytes with LMNA mutations exhibited aberrant nuclear morphology and disrupted peripheral chromatin, unlike hepatocytes or adipocytes.
- Disrupted chromatin regions were enriched for transcriptionally active genes and showed reduced LAMIN B1 interactions.
- Lamina-chromatin interactions in mutant cardiomyocytes were associated with genes from non-myocyte lineages, correlating with their increased expression.
- Human myocardium from individuals with LMNA variants displayed aberrant expression of non-myocyte pathways.
Conclusions:
- The nuclear lamina network is crucial for safeguarding cellular identity.
- Pathogenic LMNA variants disrupt peripheral chromatin, altering epigenetic and molecular characteristics.
- This disruption leads to the misexpression of genes normally found in other cell types, contributing to tissue-specific laminopathies like DCM.
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.
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