Un nouveau facteur de transcription, conservé au cours de l’évolution, qui régule la réponse inflammatoire

La réponse immunitaire est un mécanisme ancestral des organismes vivants et les voies moléculaires contrôlant l'hématopoïèse sont conservées. Le facteur de transcription Gcm est exprimé et requis dans la glie et les hémocytes des mouches, les cellules charognards agissant à l'intérieur et à l'extérieur du système nerveux central (SNC). Notre laboratoire a montré que dans les hémocytes, Gcm agit comme un inhibiteur de la voie JAK/STAT. Mon objectif était d'évaluer le rôle et la conservation évolutive du gène gcm dans le système immunitaire des mammifères. J'ai utilisé un modèle de souris mutant pour mGcm2 des cellules immunitaires du SNC, microglies. Mes résultats ont montré que mGcm2 est exprimé dans le cerveau âgé de souris. De plus, la microglie mutante mGcm2 montre une morphologie pro-inflammatoire et une expression de gènes pro-inflammatoires accrues par rapport au témoin. Ces résultats suggèrent que chez les mammifères, le Gcm possède de propriétés anti-inflammatoires.The immune response is an ancestral mechanism of living organisms and the molecular pathways controlling hematopoiesis are extremely conserved. The transcription factor Gcm is expressed and required in fly glia as well as in hemocytes, the scavenger cells acting within and outside the Central Nervous System (CNS). Our lab previously showed that in hemocytes Gcm acts as an inhibitor of the JAK/STAT and of the TOLL pathway, the latter through a novel mechanism. My aim was to assess the role and the evolutionary conservation of the gcm gene in the immune system of mammals. For this reason, I used a conditional knock out mouse model to specifically delete mGcm2 from the immune cells of the CNS, called microglia. My results showed that mGcm2 is expressed in the aged brain of mice. Furthermore, mGcm2 mutant microglia show increased pro-inflammatory morphology and expression of pro-inflammatory genes compared to the control. These results suggest that as in the flies also in mammals Gcm has important anti-inflammatory properties

Toward a Consensus in the Repertoire of Hemocytes Identified in Drosophila

International audienceThe catalog of the Drosophila immune cells was until recently limited to three major cell types, based on morphology, function and few molecular markers. Three recent single cell studies highlight the presence of several subgroups, revealing a large diversity in the molecular signature of the larval immune cells. Since these studies rely on somewhat different experimental and analytical approaches, we here compare the datasets and identify eight common, robust subgroups associated to distinct functions such as proliferation, immune response, phagocytosis or secretion. Similar comparative analyses with datasets from different stages and tissues disclose the presence of larval immune cells resembling embryonic hemocyte progenitors and the expression of specific properties in larval immune cells associated with peripheral tissues

Novel cell- and stage-specific transcriptional signatures defining <i>Drosophila</i> neurons, glia and hemocytes

specific NimA receptor, in agreement with the different environment faced by each cell types. Surprisingly, time represents a key identity parameter, as neurons, hemocytes and glia group more significantly by the stage than by the cell type and larval cells show upregulation of genes involved in chromatin organization and in DNA repair. This latter group of genes is linked to changes in gene expression levels and chromatin organization, revealing a function of these genes beyond DNA repair. Finally, the metabolic profiles reveal cell type-specific signatures and an overall shift from an embryonic, anabolic state to a larval, catabolic state

Novel cell- and stage-specific transcriptional signatures defining Drosophila neurons, glia and hemocytes

Abstract Cell types can be now defined at unprecedented resolution using high throughput assays. We analyzed the transcriptional signatures of Drosophila neurons, glia and hemocytes, as examples of cell types that are related by position (glia/neurons) or function (glia/hemocytes) or that are unrelated (neurons/hemocytes). The most related cells display the highest similarity level (neurons and glia), the least related ones, the lowest (neurons and hemocytes), however, cells can show plastic features. Glia are much more similar to neurons than to hemocytes in the embryo, but are equally similar to the two cell types in the larva, when hemocytes acquire more immune functions. Larval glia and hemocytes display common as well as specific immune features, such as the glia-specific NimA receptor, in agreement with the different environment faced by each cell types. Surprisingly, time represents a key identity parameter, as neurons, hemocytes and glia group more significantly by the stage than by the cell type and larval cells show upregulation of genes involved in chromatin organization and in DNA repair. This latter group of genes is linked to changes in gene expression levels and chromatin organization, revealing a function of these genes beyond DNA repair. Finally, the metabolic profiles reveal cell type-specific signatures and an overall shift from an embryonic, anabolic state to a larval, catabolic state

Gcm: a novel anti-inflammatory transcriptional cascade conserved from flies to humans

Innate immunity is an ancestral process that can induce pro-and anti-inflammatory states. A major challenge is to characterise the transcriptional cascades that modulate the response to chronic and acute inflammatory challenges. The Drosophila melanogaster Gcm transcription factor represents an interesting candidate for its potential anti-inflammatory role. Here we explore its evolutionary conservation and its mode of action. We found that the murine ortholog Gcm2 (mGcm2) is expressed upon aging, which is considered as a state of chronic inflammation. mGcm2 is found in a subpopulation of microglia, the innate immune cells of the central nervous system (CNS). Its expression is also induced by a lyso-phosphatidylcholine (LPC)-induced CNS demyelination (acute inflammation) and mGcm2 conditional knock out mice show an increased inflammatory phenotype upon aging or LPC injection. In agreement with the role of this transcriptional cascade in inflammation, the human ortholog hGCM2 is expressed in active demyelinating lesions of Multiple Sclerosis (MS) patients. Finally, Drosophila gcm expression is induced upon aging as well as during an acute inflammatory response and its overexpression decreases the inflammatory phenotype. Altogether, our data show that the inducible Gcm pathway is highly conserved from flies up to humans and represents a potential therapeutic anti-inflammatory target in the control of the inflammatory response

Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in beta-type hemoglobinopathy patients

BACKGROUND: Human erythropoiesis is characterized by distinct gene expression profiles at various developmental stages. Previous studies suggest that fetal-to-adult hemoglobin switch is regulated by a complex mechanism, in which many key players still remain unknown. Here, we report our findings from whole transcriptome analysis of erythroid cells, isolated from erythroid tissues at various developmental stages in an effort to identify distinct molecular signatures of each erythroid tissue. RESULTS: From our in-depth data analysis, pathway analysis, and text mining, we opted to focus on the VEGFA gene, given its gene expression characteristics. Selected VEGFA genomic variants, identified through linkage disequilibrium analysis, were explored further for their association with elevated fetal hemoglobin levels in beta-type hemoglobinopathy patients. Our downstream analysis of non-transfusion-dependent beta-thalassemia patients, beta-thalassemia major patients, compound heterozygous sickle cell disease/beta-thalassemia patients receiving hydroxyurea as fetal hemoglobin augmentation treatment, and non-thalassemic individuals indicated that VEGFA genomic variants were associated with disease severity in beta-thalassemia patients and hydroxyurea treatment efficacy in SCD/beta-thalassemia compound heterozygous patients. CONCLUSIONS: Our findings suggest that VEGFA may act as a modifier gene of human globin gene expression and, at the same time, serve as a genomic biomarker in beta-type hemoglobinopathy disease severity and hydroxyurea treatment efficacy