Biology subjects

Jullien, D.

Publications and source records attributed to Jullien, D..

3 recordsLinked to original sources

bioRxiv2025

The Mediator complex subunit Med19 extends healthy lifespan in Drosophila by preventing cellular and organismal frailty

Aging involves a progressive decline in physiological functions, often marked by the onset of a "frailty point" just before survival rates decrease rapidly. Here, we investigate how the Mediator subunit Med19 modulates this transition in Drosophila. We find that upregulating Med19 extends the median lifespan by nearly 90% and postpones the onset of accelerated mortality, suggesting that Med19 helps preserve the resilience phase of aging. In contrast, Med19 downregulation sharply reduces both median and maximum lifespan, advancing the frailty threshold. We show that Med19 knockdown increases fly vulnerability to environmental insults such as oxidative and genotoxic challenges whereas Med19 upregulation helps them resist these stresses, underscoring Med19s protective role in maintaining genomic integrity. We link these phenotypes to altered stress-response pathways at the cellular level: Med19-depleted cells show a compensatory upregulation of genes involved in iron-sulfur cluster biogenesis, glutathione metabolism, and DNA damage repair. At the cellular level, Med19 depletion triggers a "loser" phenotype in cell competition assays, activating the JNK pathway and undergoing apoptosis, highlighting a form of "cellular frailty" that parallels organismal frailty. Finally, we found that the Med19 protein level naturally decreases with age and showed that restoring Med19 expression in aged flies increases fitness and delays the onset of frailty even in older, "frail" individuals, underscoring its significance as an aging regulator. Altogether, our findings establish Med19 as a crucial mediator of lifespan and stress resilience, suggesting it acts as a rheostat that modulates the transition from healthy aging to frailty in Drosophila. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/659864v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1a5e398org.highwire.dtl.DTLVardef@14658org.highwire.dtl.DTLVardef@1b14089org.highwire.dtl.DTLVardef@41060_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- At the organismal level, Med19 upregulation extends Drosophila lifespan by 90%, delays the onset of frailty and enhances oxidative and DNA damage stress resistance, while its depletion has the opposite effect. - Med19 depletion alters the expression of stress response genes and induces a loser-cell phenotype in cell competition assays revealing its crucial function in controlling cellular fitness. - Med19 protein levels naturally decline with age, and its restoration in aged flies improves both healthspan and lifespan.

cell biology↗

bioRxiv2023

3-D deconvolution of human skin immune architecture with Multiplex Annotated Tissue Imaging System (MANTIS)

Routine clinical assays, such as conventional immunohistochemistry, often fail to resolve the regional heterogeneity of complex inflammatory skin conditions. Here we introduce MANTIS (Multiplexed Annotated Tissue Imaging System), a flexible analytic pipeline compatible with routine practice, specifically-designed for spatially-resolved immune phenotyping of the skin in experimental or clinical samples. Based on phenotype attribution matrices coupled to -shape algorithms, MANTIS projects a representative digital immune landscape, while enabling automated detection of major inflammatory clusters and concomitant single-cell data quantification of biomarkers. We observed that severe pathological lesions from systemic lupus erythematosus, Kawasaki syndrome or COVID-19-associated skin manifestations share common quantitative immune features, while displaying a non-random distribution of cells with the formation of disease-specific dermal immune structures. Given its accuracy and flexibility, MANTIS is designed to solve the spatial organization of complex immune environments to better apprehend the pathophysiology of skin manifestations.

immunology↗

bioRxiv2022

Inducible degradation of the Drosophila Mediator subunit Med19 reveals its role in regulating developmental but not constitutively-expressed genes

The multi-subunit Mediator complex plays a critical role in gene expression by bridging enhancer-bound transcription factors and the RNA polymerase II machinery. Although experimental case studies suggest differential roles of Mediator subunits, a comprehensive view of the specific set of genes regulated by individual subunits in a developing tissue is still missing. Here we address this fundamental question by focusing on the Med19 subunit and using the Drosophila wing imaginal disc as a developmental model. By coupling auxin- inducible degradation of endogenous Med19 in vivo with RNA-seq, we got access to the early consequences of Med19 elimination on gene expression. Differential gene expression analysis reveals that Med19 is not globally required for mRNA transcription but specifically regulates positively or negatively less than a quarter of the expressed genes. By crossing our transcriptomic data with those of Drosophila gene expression profile database, we found that Med19-dependent genes are highly enriched with spatially-regulated genes while the expression of most constitutively expressed genes is not affected upon Med19 loss. Whereas globally downregulation does not exceed upregulation, we identified a functional class of genes encoding spatially-regulated transcription factors, and more generally developmental regulators, responding unidirectionally to Med19 loss with an expression collapse. Moreover, we show in vivo that the Notch-responsive wingless and the E(spl)-C genes require Med19 for their expression. Combined with experimental evidences suggesting that Med19 could function as a direct transcriptional effector of Notch signaling, our data support a model in which Med19 plays a critical role in the transcriptional activation of developmental genes in response to cell signaling pathways. Author summaryThe Mediator is a large evolutionarily conserved multisubunit complex that plays essential functions in gene expression by relaying cues emanating from enhancer-bound transcription factors to the RNA polymerase II machinery. The transcriptional landscapes regulated by each Mediator subunit, especially in vivo in the context of developmental processes, remains poorly characterized. We therefore sought to provide a comprehensive view of the genes directly regulated by Med19, an archetypal Mediator subunit, in the context of the development of the Drosophila wing. Our work has important methodological implications as to carry out our analysis in the best experimental conditions, we generated mutant flies in which we could trigger fast degradation of the Med19 subunit on demand in the tissues of the living animal. We found that only a small part of the genes expressed in the developing wing are controlled by Med19 showing that this Mediator component exercises specific functions. Another major finding is the strong involvement of Med19 in the regulation of the expression of the genes involved in developmental processes supporting the idea that Med19 is a Mediator component dedicated to highly regulated mode of gene expression. The most unanticipated discovery of our study is the fact that Med19 does not appear to play a role in the expression of the genes that are constitutively transcribed, among which the housekeeping genes. This raises the notion that in the context of simple --non-regulated-- mode of expression, part of the Mediator functionalities, among which Med19, otherwise dedicated to highly regulated type of transcription, may become dispensable.

developmental biology↗