Biology subjects

Ancel, S.

Publications and source records attributed to Ancel, S..

3 recordsLinked to original sources

bioRxiv2026

Ctcf deficiency in myofibers induces pathological genome reprogramming toward the spontaneous development of myopathy

How perennial, postmitotic multinucleated tissues, such as skeletal myofibers, maintain their identity and transcriptional adaptation to homeostatic perturbations through adult life is an outstanding question. To address this issue, we investigated the consequences of loss of 3D-genome architecture in skeletal muscles by generating myofiber-specific Ctcf-deficient (CtcfmKO) mice. CtcfmKO mice did not exhibit muscular phenotype at birth but spontaneously developed a severe myopathy. Integrated analysis of snRNAseq, ATACseq and promoter-capture Hi-C revealed both common and fiber-type specific patterns of dysregulated gene expression associated with alterations in chromatin accessibility and promoter-based interactions in Ctcf-deficient myonuclei at distinct stages of myopathy development. Decreased chromatin accessibility at promoters and changes in their connectivity with distal elements were observed across all myonuclei as a direct consequence of Ctcf deficiency at early stages and associated with downregulation of genes implicated in myofiber contraction and anabolism, metabolism, adhesion and neuromuscular transmission. Conversely, at later stages, upregulation of genes leading to persistent activation of ER stress/UPR and catabolism resulted from global reconfiguration of chromatin structure and connectivity, partly as indirect consequence of Ctcf deficiency. Notably, type-IIB myonuclei exhibited specific alterations in gene expression that culminated in loss of fiber-type identity and ectopic expression of inflammatory genes. These results reveal a requirement of Ctcf for maintenance of fiber-type identity and transcriptional adaptation in vivo, through multilayered control of 3D genome integrity. They also indicate an unprecedented association between Ctcf deficiency in myofibers and susceptibility to develop myopathies, whereby Ctcf dispensability for developmental myogenesis confers vulnerability to develop myopathic syndromes.

molecular biology↗

bioRxiv2026

Patient iPSC-Derived Cartilage Organoids Reveal Defective ECM Deposition and Altered Chondrogenic Trajectory in Saul-Wilson Syndrome

Saul-Wilson syndrome (SWS) is a skeletal dysplasia characterized by primordial dwarfism and progeroid features caused by a recurrent dominant COG4 variant (p.G516R). We previously showed that this mutation accelerates Golgi retrograde trafficking and disrupts glycosylation of the proteoglycan decorin, while zebrafish models revealed defects in chondrocyte elongation and intercalation. We have also shown that the SW1353 chondrosarcoma cells carrying the SWS variant exhibit reduced secretion of extracellular matrix (ECM) components. While these results indicate a critical function of COG4 in Golgi processing, the developmental process leading to skeletal dysplasia in SWS patients remains unknown. Here, we generated patient-derived iPSC cartilage organoids (SWS organoids), modeling early human chondrogenesis. SWS organoids failed to produce cartilage structures and displayed poor expression of chondrogenic markers. Time-course RNA-seq analysis of the chondrogenic process revealed reduced activation of gene networks involved in skeletal development, ECM organization, ossification, and glycosaminoglycan metabolism. Spatial multiomic analysis of protein and glycosylation by CODEX and GLYPH imaging revealed an altered chondrogenic trajectory, persistence of mesenchymal states, global glycosylation changes, and reduced deposition of chondroitin sulfate proteoglycans. These results indicate that the COG4 mutation disrupts ECM glycosylation and chondrogenic commitment, and that SWS organoids model early defects in cartilage formation underlies impaired skeletal growth in SWS. HighlightsO_LIPatient iPSC-derived cartilage organoids model development defects in Saul-Wilson syndrome C_LIO_LISWS organoids show defective extracellular matrix deposition and attenuated chondrogenic gene expression C_LIO_LIGlycan profiling reveals global glycosylation defects and deficient proteoglycan GAG chains C_LIO_LIAn early developmental impairment in chondrogenesis alters skeletal formation in Saul-Wilson syndrome C_LI

developmental biology↗

bioRxiv2023

A Dual Color Pax7 and Myf5 In Vivo Reporter to Investigate Muscle Stem Cell Heterogeneity in Regeneration and Aging

Increasing evidence suggests heterogeneity in the muscle stem cell (MuSC) pool. In particular, a rare subset of Pax7 positive MuSCs that has never expressed the myogenic regulatory factor Myf5 has enhanced self-renewal and engraftment characteristics. However, the scarcity and limited availability of protein markers make the characterization of these cells challenging. We describe the generation of StemRep reporter mice allowing to monitor Pax7 and Myf5 protein based on equimolar levels of dual nuclear fluorescence. High levels of Pax7 protein and low levels of Myf5 delineate a deeply quiescent MuSC subpopulation with distinct molecular signatures and dynamics of activation, proliferation, and commitment. Aging decreases the number of these cells, and skews the MuSC pool towards Myf5-High cells with impaired quiescence. Altogether, we describe a novel deeply quiescent MuSC subpopulation whose maintenance is impaired in old muscles, and establish the StemRep line as a versatile tool to study quiescence and MuSC heterogeneity.

cell biology↗