Biology subjects

Metairon, S.

Publications and source records attributed to Metairon, S..

6 recordsLinked to original sources

bioRxiv2025

NNMT promotes tubular senescence and fibrosis in chronic kidney disease

Chronic kidney disease (CKD) is a major global health issue, projected to become the fifth leading cause of mortality by 2040. Renal tubular cell senescence is a key driver of kidney fibrosis, the final manifestation of CKD. However, current treatment strategies, do not target senescent cells, as the underlying mechanisms driving this dysfunctional phenotype remain poorly described. Here, we identify nicotinamide-N-methyltransferase (NNMT), as a critical mediator of tubular senescence and fibrosis in CKD. Using human RNAseq profiles of CKD, we show that NNMT expression in the renal tubulointerstitium is strongly associated with CKD pathology and transcriptional signatures of cellular senescence. In human diabetic kidney disease biopsies, NNMT levels correlate with the senescence marker p21, kidney function decline, and fibrosis. Spatial transcriptomics further highlights that NNMT-positive tubules are senescent, fibrotic, and surrounded by a pro-inflammatory microenvironment. Preclinical models of early-stage CKD, show upregulation of NNMT and association with senescence. Overexpression of NNMT in TGF-{beta}-stimulated tubular epithelial cells promotes senescence and partial epithelial-to-mesenchymal transition (EMT), while inhibition of NNMT in kidney cells and organoids is protective. Altogether, we identify NNMT as a novel therapeutic target in the early stages of CKD with the potential to reduce tubular senescence, fibrosis and significantly slow disease progression.

cell biology↗

bioRxiv2023

The genome and population genomics of allopolyploid Coffea arabica reveal the diversification history of modern coffee cultivars

Coffea arabica, an allotetraploid hybrid of C. eugenioides and C. canephora, is the source of approximately 60% of coffee products worldwide, and its cultivated accessions have undergone several population bottlenecks. We present chromosome-level assemblies of a di-haploid C. arabica accession and modern representatives of its diploid progenitors, C. eugenioides and C. canephora. The three species exhibit largely conserved genome structures between diploid parents and descendant subgenomes, with no obvious global subgenome dominance. We find evidence for a founding polyploidy event 350,000-610,000 years ago, followed by several pre-domestication bottlenecks, resulting in narrow genetic variation. A split between wild accessions and cultivar progenitors occurred [~]30.5 kya, followed by a period of migration between the two populations. Analysis of modern varieties, including lines historically introgressed with C. canephora, highlights their breeding histories and loci that may contribute to pathogen resistance, laying the groundwork for future genomics-based breeding of C. arabica.

genomics↗

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↗

bioRxiv2022

Mice with humanized livers reveal the involvement of hepatocyte circadian clocks in rhythmic behavior and physiology

The circadian clock is an evolutionarily acquired gene network that synchronizes physiological processes to adapt homeostasis to the succession of day and night. While most mammalian cells have a circadian clock, their synchronization at the body-level depends on a central pacemaker located in the suprachiasmatic nuclei of the hypothalamus that integrates light signals. However, peripheral organs are also synchronized by feeding cues that can uncoupled them from the central pacemaker. Nevertheless, the potential feedback of peripheral signals on the central clock remains poorly characterized. To discover whether peripheral organ circadian clocks may affect the central pacemaker, we used a chimeric model in which mouse hepatocytes were replaced by human hepatocytes. These human hepatocytes showed a specific rhythmic physiology caused by their blunted response to mouse systemic signals. Strikingly, mouse liver humanization reprogrammed the liver diurnal gene expression and modified the phase of the circadian clock. The phase advance was also reflected in the muscle as well as the entire rhythmic physiology of the animals, indicating an impact on the circadian function of the central clock. Like mice with a deficient central clock, the humanized animals shifted their rhythmic physiology more rapidly to the light phase under day feeding. Our results indicate that peripheral clocks may affect the central pacemaker and offer new perspectives to understand the impact of peripheral clocks on the global circadian physiology.

physiology↗

bioRxiv2020

In-vivo Transcriptomic Profiling of Systemic Aging using Cell Encapsulation

Sustained exposure to a young systemic environment rejuvenates aged organisms and promotes cellular function. However, due to the intrinsic complexity of tissues it remains challenging to pinpoint niche-independent effects of circulating factors on specific cell populations. Here we describe a method for the encapsulation of human and mouse skeletal muscle progenitors in diffusible polyethersulfone hollow fiber capsules that can be used to profile systemic aging in vivo independent of heterogeneous short-range tissue interactions. We observed that circulating long-range signaling factors in the old systemic environment lead to an activation of Myc and E2F transcription factors, induce senescence and suppress myogenic differentiation. Importantly, in vitro profiling using young and old serum in 2D culture does not capture all pathways deregulated in encapsulated cells in aged mice. Thus, in vivo transcriptomic profiling using cell encapsulation allows for the characterization of effector pathways of systemic aging with unparalleled accuracy.

bioengineering↗

bioRxiv2018

AMPK promotes induction of a tumor suppressor FLCN through activation of TFEB independently of mTOR

AMP-activated protein kinase (AMPK) is a central energy sensor and master regulator of energy homeostasis. AMPK not only elicits acute metabolic responses, but also promotes metabolic reprogramming and adaptions in the long-term through regulation of specific transcription factors/co-activators. We performed a whole-genome transcriptome profiling in wild-type and AMPK-deficient mouse embryonic fibroblasts (MEF) and mouse primary hepatocytes that had been treated with two distinct classes of small-molecule AMPK activators, namely 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or 991. This led to the identification of distinct compound-dependent gene expression signatures and to the discovery of several AMPK-regulated genes, including folliculin (Flcn), a gene encoding for a tumor suppressor and nutrient sensor. Gene set enrichment and pathway analyses identified the lysosomal pathway and the associated transcription factor EB (TFEB) as key transcriptional mediator responsible for AMPK-dependent gene expression changes. AMPK-induced Flcn expression was abolished in TFEB/TFE3 double knockout MEF and the promoter activity of Flcn was profoundly reduced when its putative TFEB-binding site was mutated. Mechanistically, we have found that AMPK promotes the dephosphorylation and nuclear localization of TFEB independently of mTOR activity.\n\nCollectively, we identified the AMPK-TFEB-FLCN axis as a potential key regulator for cellular and metabolic homeostasis. Moreover, data from zebrafish with physiologically and pharmacologically activated AMPK confirmed the AMPK-TFEB-FLCN cascade in vivo.

molecular biology↗