Biology subjects

Durand, C.

Publications and source records attributed to Durand, C..

3 recordsLinked to original sources

bioRxiv2026

A PERK/FOXO1 AXIS LINKS DNA DAMAGE TO FIBROBLAST SURVIVAL IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS

ObjectiveDiffuse cutaneous systemic sclerosis (dcSSc) is a life-limiting fibrotic disease. We and others have shown that dcSSc fibroblasts accumulate numerous somatic mutations associated with senescence-like features; however, the mechanism(s) enabling their survival remain unclear. MethodsSkin biopsies were obtained from lesional tissues from dcSSc (n=10), dcSSc treated with autologous hematopoietic stem cell transplantation (ASCT, n=8) or 7 age/sex-matched healthy controls. Primary dermal fibroblasts were generated from biopsies. Spatial RNA sequencing, immunoblotting, confocal microscopy, and functional assays were used to mechanistically delineate signaling pathways linking DNA-damage with fibroblast survival. ResultsdcSSc fibroblasts demonstrated increased pH2AX DNA double-strand-break foci yet remained apoptosis resistant. These cells displayed features of metabolic-stress remodeling, including mitochondrial hyperpolarization, increased reactive oxygen species production, and enhanced mitochondrial biogenesis. Spatial transcriptomics and subsequent biochemical analyses identified activation of a PERK/ATF4/FOXO1 axis, characterized by PERK phosphorylation, selective ATF4 translation, FOXO1 nuclear translocation, and induction of downstream antioxidant and metabolic programs. In contrast, fibroblasts from post-ASCT patients exhibited normalization of DNA-damage markers and mitochondrial parameters without ATF4/FOXO1 activation. Pharmacologic inhibition of either PERK or FOXO1 selectively restored mitochondrial-dependent apoptosis in dcSSc fibroblasts, demonstrating that this axis is required for their survival following extensive genomic injury. ConclusiondcSSc fibroblasts persist despite substantial genomic injury by engaging a PERK/ATF4/FOXO1 metabolic-adaptation program that suppresses mitochondrial-dependent apoptosis. This survival axis is not present after ASCT. Targeting PERK or FOXO1 restores apoptosis selectively in dcSSc fibroblasts, highlighting its potential use as a therapeutic target for eliminating pathogenic senescence-like fibroblasts in dcSSc. HighlightsO_LIBoth ex-vivo skin and in-vitro primary dermal fibroblasts derived from dcSSc patients have a higher frequency of intrinsic DNA damage signals and senescence-associated features; yet they evade mitochondrial-dependent apoptosis. C_LIO_LIPathogenic dcSSc fibroblasts rewire their metabolism, characterized by mitochondrial hyperpolarization and elevated ROS. C_LIO_LISpatial transcriptomics and functional analyses reveal a PERK/ATF4/FOXO1 stress-adaptation axis that drives fibroblast survival in dcSSc. C_LIO_LIThis maladaptive survival program characterized by increased genotoxic stress, and mitochondrial remodelling is absent in post-ASCT fibroblasts. C_LIO_LITargeting PERK or FOXO1 selectively sensitizes dcSSc fibroblasts to apoptosis revealing a potential promising therapeutic strategy in dcSSc. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/706443v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1b3f791org.highwire.dtl.DTLVardef@42548aorg.highwire.dtl.DTLVardef@bc4ce1org.highwire.dtl.DTLVardef@5b4d48_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

Genome-wide analyses reveal a strong association between LEPR gene variants and body fat reserves in ewes

Among the adaptive capacities of animals, the management of energetic body reserves (BR) through the BR mobilization and accretion processes (BR dynamics, BRD) has become an increasingly valuable attribute for livestock sustainability, allowing animals to cope with more variable environments. BRD has previously been reported to be heritable in ruminants. In the present study, we conducted genome-wide studies (GWAS) in sheep to determine genetic variants associated with BRD. BR levels and BR changes over time were obtained through body condition score measurements at eight physiological stages throughout each productive cycle in Romane ewes (n=1034) and were used as phenotypes for GWAS. After quality controls and imputation, 48,513 single nucleotide polymorphisms (SNP) were included in the GWAS. Among the QTLs identified, a major QTL associated with BR levels during pregnancy and lactation was identified on chromosome 1. In this region, several significant SNPs mapped to the leptin receptor gene (LEPR), among which one SNP mapped to the coding sequence. The point mutation induces the p.P1019S substitution in the cytoplasmic domain, close to tyrosine phosphorylation sites. The frequency of the SNP associated with increased BR levels was 32%, and the LEPR genotype explained up to 5% of the variance of the trait. These results provide strong evidence for involvement of LEPR in the regulation of BRD in sheep and highlight it as a major candidate for improving adaptive capacities.

genetics↗

bioRxiv2021

Stress-induced collective behavior leads to the formation of multicellular structures and the survival of the unicellular alga Chlamydomonas

Depending on their nature, living organisms use various strategies to adapt to environmental stress conditions. Multicellular organisms implement a set of reactions involving signaling and cooperation between different types of cells. Unicellular organisms on the other hand must activate defense systems, which involve collective behaviors between individual organisms. In the unicellular model alga Chlamydomonas reinhardtii, the existence and the function of collective behavior mechanisms in response to stress remain largely unknown. Here we report the discovery of a mechanism of abiotic stress response that Chlamydomonas can trigger to form large multicellular structures that can comprise several thousand cells. We show that these aggregates constitute an effective bulwark within which the cells are efficiently protected from the toxic environment. We have generated the first family of mutants that aggregate spontaneously, the socializer mutants (saz), of which we describe here in detail saz1. We took advantage of the saz mutants to implement a large scale multiomics approach that allowed us to show that aggregation is not the result of passive agglutination, but rather genetic reprogramming and substantial modification of the secretome. The reverse genetic analysis we conducted on some of the most promising candidates allowed us to identify the first positive and negative regulators of aggregation and to make hypotheses on how this process is controlled in Chlamydomonas.

plant biology↗