Biology subjects

Lefebvre, V.

Publications and source records attributed to Lefebvre, V..

7 recordsLinked to original sources

bioRxiv2026

SOX4 Reprograms Adipose Stromal Cells into a Cancer-Associated Fibroblast-like State to Drive Metabolic Disease

Pathogenic adipose tissue remodeling promotes metabolic disease in obesity, but the mechanisms that establish this unhealthy tissue state remain poorly understood. Here, we show that obesity drives SOX4-dependent reprogramming of mesenchymal stromal cells (MSCs) into cancer-associated fibroblast-like (CAF-like) cells that promote adipose tissue dysfunction. TGF{beta} signaling is elevated in obesity and activates SOX4 in mouse and human MSCs, inducing their conversion to a CAF-like state. In mice, MSC-specific SOX4 activation induces the CAF-like program and exacerbates adipose tissue inflammation and glucose intolerance, whereas Sox4 deletion attenuates inflammation and improves glucose homeostasis during obesity. We further identify the growth factor Midkine (MDK) as a SOX4-regulated paracrine effector produced by CAF-like cells. MDK inhibition in obese mice reduces adipose tissue inflammation and improves metabolic function. Together, these findings define a TGF{beta}-SOX4-MDK stromal signaling axis that drives pathological adipose tissue remodeling in obesity and highlight this pathway as a potential therapeutic target for improving metabolic health.

cell biology↗

bioRxiv2026

The SoxC transcription factors regulate multiple early retinal lineages and function in parallel with Atoh7 to promote retinal ganglion cell genesis

Retinal development is orchestrated by a network of transcription factors that guide multipotent retinal progenitor cells (RPCs) to fate-committed lineages, ultimately producing seven major retinal cell classes. Among these, retinal ganglion cells (RGCs) serve as the sole output neurons of the retina, relaying visual and non-visual information to the brain. RGC specification requires a cascade of transcriptional regulators, including the basic helix-loop-helix (bHLH) factor Atoh7, which confers competence to RPCs, and Pou4f2 and Isl1, which drive terminal differentiation and subtype diversification. Previous studies demonstrate that the SoxC group transcription factors (Sox4, Sox11, and Sox12) are also involved in RGC genesis, but their precise integration into the Atoh7-driven regulatory hierarchy remains undefined. To address this question, we used the retina-specific Vsx2-Cre line to generate Sox4/Sox11 double conditional knockout (dcKO) and Sox4/Sox11/Atoh7 triple knockout (tKO) mice. Immunohistochemistry revealed profound lineage disruption and reduced progenitor proliferation and survival in both dcKO and tKO retinas; not only RGC genesis but also that of horizontal and amacrine (H&As) cells were severely compromised, whereas photoreceptor cells (PHCs) production increased. These results indicate that Sox4 and Sox11 are involved in the coordinated generation of the different early retinal lineages. Like the Atoh7-null retina, RGC precursors still formed in the SoxC dcKO retina, but their genesis was almost completely abolished in the tKO retina. Our findings indicate that the SoxC factors act in parallel with Atoh7 as a major upstream regulatory input to initiate RGC fate. Bulk RNA-seq revealed the SoxC-dependent transcriptional programs and signaling pathways and confirmed the lineage changes demonstrated by marker analysis. CUT&Tag analysis identified the genome-wide binding sites and thereby the target genes of Sox11, further illuminating the mechanisms underlying functions of the SoxC factors in multiple retinal cell states/types during development.

developmental biology↗

bioRxiv2026

Evolution of regulatory chromatin contacts: insights from duplicated genes

In multicellular organisms, gene expression is controlled by numerous cis-regulatory elements that can be located far away from their target genes on the linear genome. Interactions between gene promoters and distant regulatory elements take place through chromatin contacts or loops. While other aspects of gene expression regulation have been well studied from an evolutionary perspective, regulatory chromatin contact evolution remains largely unexplored, due to a lack of comparable data across species. Here, we study the evolution of regulatory chromatin contacts by focusing on duplicated genes in the mouse genome. We use an extensive collection of high resolution promoter-centered Hi-C data to define promoter-enhancer chromatin contacts for 1,420 pairs of duplicated genes and to study their evolutionary divergence, in conjunction with the evolutionary divergence of their expression patterns. We show that chromatin contacts evolve faster than expression patterns, as previously observed for other gene regulation mechanisms. We show that duplicated gene localisation in cis or in trans is strongly associated with chromatin contact divergence. We find a significant correlation between expression divergence and chromatin contact divergence across duplicated gene pairs. Our results highlight the complex evolutionary dynamics of regulatory chromatin contacts and the association between chromatin contact evolution and gene expression evolution, across a broad time scale.

evolutionary biology↗

bioRxiv2025

Sox4 in Treg Cells Suppresses IL-10 Production via c-Maf Degradation and Exacerbates Type 2 Inflammation

The anti-inflammatory cytokine interleukin-10 (IL-10) produced by regulatory T (Treg) cells plays a crucial role in regulating allergic airway inflammation. However, the mechanisms governing IL-10 production in Treg cells remain unclear. In this study, we first identified Sox4 as a gene whose expression is down-regulated in IL-10-producing Treg cells. Comprehensive gene expression profiling of Sox4-deficient Treg cells and Sox4-overexpressing Treg cells revealed specific downregulation of Il10 and Ctla4 by Sox4. Sox4-deficient Treg cells exhibited increased IL-10 production and CTLA-4 expression both in vitro and in vivo and strongly suppressed Th2 cell proliferation compared with Sox4-expressing Treg cells. In a house dust mite (HDM)-induced asthma model, Treg-specific Sox4-deficient (Sox4-cKO) mice exhibited IL-10-dependent reductions in eosinophilic inflammation and Th2 cell infiltration in the airways. A comparison of Sox4-cKO and wild-type Treg cells in the same inflamed environment in mixed bone marrow chimeric mice with HDM-induced asthma revealed that Sox4-mediated suppression of c-Maf is cell-intrinsic. In addition, overexpression of Sox4 in Treg cells repressed the activation of c-Maf-regulated chromatin regions, including those around the Il10 and Ctla4 loci. Moreover, Sox4-induced suppression of IL-10 and CTLA-4 in Treg cells was rescued by forced expression of c-Maf. While Sox4 did not significantly affect Maf mRNA levels, Sox4 degraded c-Maf proteins in Treg cells through its 33 C-terminal residues. Via a domain distinct from its C-terminus, Sox4 physically interacted with c-Maf, subsequently facilitating its degradation through a ubiquitin-proteasome pathway. These findings elucidate a mechanism by which Sox4 influences the asthmatic responses by regulating the c-Maf/IL-10 axis in lung Treg cells.

immunology↗

bioRxiv2023

Do NSm virulence factors in the Bunyavirales order originate from Gn gene duplication?

One-third of the nine WHO shortlisted pathogens prioritized for research and development in public health emergencies belong to the Bunyavirales order. Several Bunyavirales species carry an NSm protein that acts as a virulence factor. We predicted the structures of these NSm protein and unexpectedly found that in two families, its cytosolic domain is inferred to have a similar fold to the cytosolic domain of the viral envelope-forming glycoprotein N (Gncyto) encoded on the same genome fragment. We show that although the sequence identity between the NSmcyto and Gncyto domains is low, the conservation of the two zinc finger-forming CCHC motifs explains the predicted structural conservation. Importantly, our predictions provide a first glimpse into the long unknown structure of NSm and its link to virulence. Also, these predictions suggest that NSm is the result of a gene duplication event in the Bunyavirales Nairoviridae and Peribunyaviridae families, and that such events may be common in the recent evolutionary history of RNA viruses.

bioinformatics↗

bioRxiv2021

The pH-dependent processivity of Arabidopsis AtPME2 can control cell wall mechanical properties

Pectin methylesterases (PMEs) modify homogalacturonans (HG) chemistry and play a key role in regulating primary cell wall mechanical properties. How PME activity can fine-tune pectin structure in the growing plant has remained elusive. Here we report on the Arabidopsis AtPME2, which we found to be highly expressed during lateral root emergence and dark-grown hypocotyl elongation. We produced the mature active enzyme using heterologous expression in Pichia pastoris and characterized it through the use of a generic plant PME antiserum suitable for detecting recombinant and native enzyme independent of species source. At neutral pH AtPME2 is preferentially active on pectins with a degree of 55-70% methylesterification and can be inhibited by PME inhibitor protein (PMEI). We show that the mode of action for AtPME2 can switch from full processivity (at pH 8), creating large blocks of unmethylated galacturonic acid, to low processivity (at pH 5) and relate these observations to the differences in electrostatic potential of the protein at acidic and alkaline pH. To assess the role of AtPME2 in development, we characterized two knock-out lines. We show that in the context of acidified apoplast, low-processive demethylesterification by AtPME2 can loosen the cell wall, with consequent increase in cell elongation and etiolated hypocotyl length. Our study brings insights into how the pH-dependent regulation by PME activity could affect pectin structure and associated cell wall mechanical properties in expansion. One sentence summaryThe processivity of AtPME2, a pectin methylesterase that fine-tunes cell wall pectins is modulated by pH in vitro and impacts the mechanical properties of the wall, affecting development in planta.

plant biology↗

bioRxiv2021

The quasi-universality of nestedness in the structure of quantitative plant-parasite interactions

AO_SCPLOWBSTRACTC_SCPLOWUnderstanding the relationships between host range and pathogenicity for parasites, and between the efficiency and scope of immunity for hosts are essential to implement efficient disease control strategies. In the case of plant parasites, most studies have focused on describing qualitative interactions and a variety of genetic and evolutionary models has been proposed in this context. Although plant quantitative resistance benefits from advantages in terms of durability, we presently lack models that account for quantitative interactions between plants and their parasites and the evolution of these interactions. Nestedness and modularity are important features to unravel the overall structure of host-parasite interaction matrices. Here, we analysed these two features on 32 matrices of quantitative pathogenicity trait data gathered from 15 plant-parasite pathosystems consisting of either annual or perennial plants along with fungi or oomycetes, bacteria, nematodes, insects and viruses. The performance of several nestedness and modularity algorithms was evaluated through a simulation approach, which helped interpretation of the results. We observed significant modularity in only six of the 32 matrices, with two or three modules detected. For three of these matrices, modules could be related to resistance quantitative trait loci present in the host. In contrast, we found high and significant nestedness in 30 of the 32 matrices. Nestedness was linked to other properties of plant-parasite interactions. First, pathogenicity trait values were explained in majority by a parasite strain effect and a plant accession effect, with no or minor parasite-plant interaction term. Second, correlations between the efficiency and scope of the resistance of plant genotypes, and between the host range breadth and pathogenicity level of parasite strains were overall positive. This latter result questions the efficiency of strategies based on the deployment of several genetically-differentiated cultivars of a given crop species in the case of quantitative plant immunity.

pathology↗