Biology subjects

Joliot, V.

Publications and source records attributed to Joliot, V..

4 recordsLinked to original sources

bioRxiv2025

Epigenetic control of nuclear mechanics and cellular migration via histone H3 lysine 9 methylation at Lamina-Associated Domains

Chromatin not only stores genetic information but also regulates nuclear mechanical properties. However, how epigenetic modifications, such as histone H3 lysine 9 trimethylation (H3K9me3), shape chromatin states at lamina-associated domains (LADs) and influence nuclear mechanics remains unclear. Here, we reveal an unexpected and paradoxical role of the pro-oncogenic H3K9 lysine methyltransferase (KMT) SETDB1, frequently overexpressed in many cancers, in LAD regulation. Rather than reinforcing heterochromatin, SETDB1 overexpression prevents SUV39H1-driven H3K9me3 accumulation at LADs, thereby disrupting the peripheral heterochromatin. Reducing SETDB1 levels, or disrupting its interaction with SUV39H1, enables SUV39H1 to restore LAD-localized H3K9me3 and re-establish an epithelial-like heterochromatin architecture. Heterochromatin reorganization upon SETDB1 reduction stiffens the nucleus and increases cell viscosity, thereby reducing cancer cell deformability and migratory capacity. Strikingly, these mechanical effects occur without major transcriptional changes, demonstrating that chromatin architecture itself critically shapes nuclear mechanics and cell motility. Our findings reveal a previously unrecognized role of the SETDB1-SUV39H1 axis in nuclear biomechanics, highlighting it as a potential determinant of cancer cell migration and metastatic processes.

molecular biology↗

bioRxiv2025

EMILIN1 emerges as a TGFbeta/SETDB1-regulated secreted biomarker in Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is an incurable muscle-wasting disorder characterized by chronic membrane damage, inflammation, and progressive fibrosis. Fibrosis in DMD is driven by sustained TGF{beta} signaling, which promotes extracellular matrix (ECM) accumulation. We previously showed that SETDB1 sustains the TGF{beta}-induced fibrotic response in DMD myotubes. Here, we further show that SETDB1 modulates the TGF{beta}-induced secretome, particularly by regulating ECM-related proteins. Comparison of the basal secretome from DMD patient-derived myotubes and healthy controls revealed a distinct disease-specific profile. Integrating both secretome analyses, we identified EMILIN1, an ECM glycoprotein not previously studied in skeletal muscle, as a robust shared candidate; EMILIN1 is enriched in the DMD secretome, further upregulated by TGF{beta}, and downregulated upon SETDB1 depletion. We confirmed EMILIN1 overexpression in DMD patient muscle biopsies, validating its pathological relevance. Functionally, EMILIN1 depletion modulated myogenic differentiation and reduced expression of the fibrotic marker SERPINE1. These findings establish EMILIN1 as a novel secreted regulator of myogenesis and fibrosis, and implicate SETDB1 in shaping the TGF{beta}-dependent secretome in DMD. Our integrative proteomic approach provides new insights into the molecular drivers of impaired regeneration in DMD and highlights potential therapeutic targets.

genetics↗

bioRxiv2023

SETDB1 modulates the TGFbeta response in Duchenne muscular dystrophy myotubes

Overactivation of the TGF{beta} signaling in Duchenne muscular dystrophy (DMD) is a major hallmark of disease progression, leading to fibrosis and muscle dysfunction. Here, we investigated the role of SETDB1, a histone lysine methyltransferase involved in muscle differentiation. Our data show that, following TGF{beta} induction, SETDB1 accumulates in the nuclei of healthy myotubes, while being already present in the nuclei of DMD myotubes where TGF{beta} signaling is constitutively activated. Interestingly, transcriptomics revealed that depletion of SETDB1 in DMD myotubes leads to downregulation of TGF{beta}-target genes coding for secreted factors involved in extracellular matrix remodeling and inflammation. Consequently, SETDB1 silencing in DMD myotubes abrogates the deleterious effect of their secretome on myoblast differentiation by impairing myoblast pro-fibrotic response. Our findings indicate that SETDB1 potentiates the TGF{beta}-driven fibrotic response in DMD muscles, providing a new axis for therapeutic intervention. Key resultsO_LITGF{beta} induces nuclear accumulation of SETDB1 in healthy myotubes C_LIO_LISETDB1 is enriched in DMD myotube nuclei with intrinsic TGF{beta} pathway overactivation C_LIO_LISETDB1 LOF in DMD myotubes attenuates TGF{beta}-induced pro-fibrotic response C_LIO_LISecretome of TGF{beta}-treated DMD myotubes with SETDB1 LOF is less deleterious on myoblast differentiation C_LI

cell biology↗

bioRxiv2021

SETDB1 Fuels the Lung Cancer Phenotype by Modulating Epigenome, 3D Genome Organization and Chromatin Mechanical Properties

Imbalance in the finely orchestrated system of chromatin-modifying enzymes is a hallmark of many pathologies such as cancers, since causing the affection of the epigenome and transcriptional reprogramming. Here, we demonstrate that a loss-of-function mutation (LOF) of the major histone lysine methyltransferase SETDB1 possessing oncogenic activity in lung cancer cells leads to broad changes in the overall architecture and mechanical properties of the nucleus through genome-wide redistribution of heterochromatin, which perturbs chromatin spatial compartmentalization. Together with the enforced activation of the epithelial expression program, cytoskeleton remodeling, reduced proliferation rate and restricted cellular migration, this leads to the reversed oncogenic potential of lung adenocarcinoma cells. These results emphasize an essential role of chromatin architecture in the determination of oncogenic programs and illustrate a relationship between gene expression, epigenome, 3D genome and nuclear mechanics.

cancer biology↗