Biology subjects

Zuela - Sopilniak, N.

Publications and source records attributed to Zuela - Sopilniak, N..

4 recordsLinked to original sources

bioRxiv2024

Multi-level transcriptomic analysis of LMNA-related dilated cardiomyopathy identifies disease-driving processes

Mutations in the LMNA gene, which encodes the nuclear envelope (NE) proteins lamins A and C, cause dilated cardiomyopathy (LMNA-DCM) and other diseases. The pathogenic mechanisms for LMNA-DCM remain poorly understood, limiting current treatment options and leading to high mortality amongst patients. We developed a mouse model with inducible, cardiomyocyte-specific Lmna deletion (cKO) and performed comprehensive bulk, single-nucleus, and spatial transcriptomic analyses across disease progression. Our analysis identified key disease-driving genes involved in cellular responses to DNA damage, cytosolic pattern recognition receptor signaling, and innate immunity that originated from two disease-specific cardiomyocyte subpopulations. Spatial mapping revealed aberrant interactions between these cardiomyocytes, fibroblasts, and immune cells, contributing to tissue-wide transcriptional changes in cKO hearts. Concurrent cardiomyocyte-specific disruption of the LINC complex, which transmits cytoskeletal forces to the nucleus, substantially reduced NE rupture in cKO cardiomyocytes, normalized expression of more than half of the dysregulated genes, and dramatically improved cardiac function and survival in cKO mice. These findings suggest that NE rupture in cKO cardiomyocytes triggers cytosolic DNA sensing pathways and maladaptive cell-cell communication with fibroblasts and immune cells, leading to fibrosis and inflammation driving LMNA-DCM pathogenesis.

cell biology↗

bioRxiv2024

Microtubule forces drive nuclear damage in LMNA cardiomyopathy

Nuclear homeostasis requires a balance of forces between the cytoskeleton and nucleus. Mutations in the LMNA gene, which encodes the nuclear envelope proteins lamin A/C, disrupt this balance by weakening the nuclear lamina. This results in nuclear damage in contractile tissues and ultimately muscle disease. Intriguingly, disrupting the LINC complex that connects the cytoskeleton to the nucleus has emerged as a promising strategy to ameliorate LMNA-associated cardiomyopathy. Yet how LINC complex disruption protects the cardiomyocyte nucleus remains unclear. To address this question, we developed an assay to quantify the coupling of cardiomyocyte contraction to nuclear deformation and interrogated its dependence on the nuclear lamina and LINC complex. We found that, surprisingly, the LINC complex was mostly dispensable for transferring contractile strain to the nucleus, and that increased nuclear strain in lamin A/C-deficient cardiomyocytes was not rescued by LINC complex disruption. Instead, LINC complex disruption eliminated the cage of microtubules encircling the nucleus. Disrupting microtubules was sufficient to prevent nuclear damage and rescue cardiac function induced by lamin A/C deficiency. We computationally simulated the stress fields surrounding cardiomyocyte nuclei and show how microtubule forces generate local vulnerabilities that damage lamin A/C-deficient nuclei. Our work pinpoints localized, microtubule-dependent force transmission to the nucleus as a pathological driver and therapeutic target for LMNA- cardiomyopathy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/579774v5_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1443daeorg.highwire.dtl.DTLVardef@12d7a8borg.highwire.dtl.DTLVardef@c85900org.highwire.dtl.DTLVardef@14b3c89_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer

Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells have lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells altered expression of numerous other proteins implicated in metastatic progression. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels and decreased disease-free survival. These findings suggest that downregulation of lamin A/C may influence both biochemical and physical properties of the cell to promote breast cancer metastatic progression.

cancer biology↗

bioRxiv2019

Molecular dissection of the cellular response to mechanical stress

The response of cells to mechanical stress is crucial for many cellular functions, yet its molecular mechanisms are not yet fully understood. Previous studies of the cellular response to mechanical stress were performed on cultured cells or isolated muscle fibers devoid of cell and/or tissue contexts. Thus, the emerging results were limited to the specific cell types or tissues analyzed and dependent on the growth matrix elasticity. In the present study, we looked for changes in early gene expression in response to mechanical whole body stretching of living C. elegans. Our transcriptome analysis revealed upregulation of genes involved in cuticle development, stress response and several signaling pathways such as WNT, TGF{beta}, AMPK and Hedgehog signaling. These findings indicate that protecting against mechanical insults entails providing additional support to the mechanically resilient protective cuticle, and that proper recovery from mechanical stretching requires an intact Hedgehog signaling pathway. Recent findings suggest an important role for the nuclear lamina in mediating cellular mechanical response. The nuclear lamina is composed mainly of lamins, which are nuclear intermediate filament-type proteins needed, among other functions to maintain nuclear integrity. One particular area of interest are laminopathies, which are caused by mutations in lamin. Stretched animals expressing the Emery Dreifuss Muscular Dystrophy (EDMD) linked L535P lamin mutation, showed further upregulation of cytoskeleton organization, cellular respiration and mitochondrial protein-unfolding stress response genes, most likely to compensate for aberrant muscle tissue function. These findings provide a broad multi-dimensional picture of the in vivo genetic response of live animals to mechanical stress, highlighting previously unreported mechano-sensitive genes and molecular pathways.

genetics↗