Le contrôle de l'identité à travers les âges

Garnier Ludovic, Lebas Fabien, Leger Claire, Lemoine Raphaëlle, Marcilly Matthieu, Mellal Fatiha, Paillat Xavier, Vercelonne Samuel, Verge Mélanie. Le contrôle de l'identité à travers les âges. In: Revue juridique de l'Ouest, 2012-3. pp. 343-362

IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans

International audienceHepatic fibrosis arises from inflammation in the liver initiated by resident macrophage activation and massive leukocyte accumulation. Hepatic macrophages hold a central position in maintaining homeostasis in the liver and in the pathogenesis of acute and chronic liver injury linked to fibrogenesis. Interferon regulatory factor 5 (IRF5) has recently emerged as an important proinflammatory transcription factor involved in macrophage activation under acute and chronic inflammation. Here, we revealed that IRF5 is significantly induced in liver macrophages from human subjects developing liver fibrosis from nonalcoholic fatty liver disease or hepatitis C virus infection. Furthermore, IRF5 expression positively correlated with clinical markers of liver damage, such as plasma transaminase and bilirubin levels. Interestingly, mice lacking IRF5 in myeloid cells (MKO) were protected from hepatic fibrosis induced by metabolic or toxic stresses. Transcriptional reprogramming of macrophages lacking IRF5 was characterized by immunosuppressive and antiapoptotic properties. Consequently, IRF5 MKO mice respond to hepatocellular stress by promoting hepatocyte survival, leading to complete protection from hepatic fibrogenesis. Our findings reveal a regulatory network, governed by IRF5, that mediates hepatocyte death and liver fibrosis in mice and humans. Therefore, modulating IRF5 function may be an attractive approach to experimental therapeutics in fibroinflammatory liver disease

Loss of G protein pathway suppressor 2 in human adipocytes triggers lipid remodeling by upregulating ATP binding cassette subfamily G member 1

International audienceObjective: Adipogenesis is critical for adipose tissue remodeling during the development of obesity. While the role of transcription factors in the orchestration of adipogenic pathways is already established, the involvement of coregulators that transduce regulatory signals into epigenome alterations and transcriptional responses remains poorly understood. The aim of our study was to investigate which pathways are controlled by G protein pathway suppressor 2 (GPS2) during the differentiation of human adipocytes.Methods: We generated a unique loss-of-function model by RNAi depletion of GPS2 in human multipotent adipose-derived stem (hMADS) cells. We thoroughly characterized the coregulator depletion-dependent pathway alterations during adipocyte differentiation at the level of transcriptome (RNA-seq), epigenome (ChIP-seq H3K27ac), cistrome (ChIP-seq GPS2), and lipidome. We validated the in vivo relevance of the identified pathways in non-diabetic and diabetic obese patients.Results: The loss of GPS2 triggers the reprogramming of cellular processes related to adipocyte differentiation by increasing the responses to the adipogenic cocktail. In particular, GPS2 depletion increases the expression of BMP4, an important trigger for the commitment of fibroblast-like progenitors toward the adipogenic lineage and increases the expression of inflammatory and metabolic genes. GPS2-depleted human adipocytes are characterized by hypertrophy, triglyceride and phospholipid accumulation, and sphingomyelin depletion. These changes are likely a consequence of the increased expression of ATP-binding cassette subfamily G member 1 (ABCG1) that mediates sphingomyelin efflux from adipocytes and modulates lipoprotein lipase (LPL) activity. We identify ABCG1 as a direct transcriptional target, as GPS2 depletion leads to coordinated changes of transcription and H3K27 acetylation at promoters and enhancers that are occupied by GPS2 in wild-type adipocytes. We find that in omental adipose tissue of obese humans, GPS2 levels correlate with ABCG1 levels, type 2 diabetic status, and lipid metabolic status, supporting the in vivo relevance of the hMADS cell-derived in vitro data.Conclusion: Our study reveals a dual regulatory role of GPS2 in epigenetically modulating the chromatin landscape and gene expression during human adipocyte differentiation and identifies a hitherto unknown GPS2-ABCG1 pathway potentially linked to adipocyte hypertrophy in humans

IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans

Hepatic fibrosis arises from inflammation in the liver initiated by resident macrophage activation and massive leukocyte accumulation. Hepatic macrophages hold a central position in maintaining homeostasis in the liver and in the pathogenesis of acute and chronic liver injury linked to fibrogenesis. Interferon regulatory factor 5 (IRF5) has recently emerged as an important proinflammatory transcription factor involved in macrophage activation under acute and chronic inflammation. Here, we revealed that IRF5 is significantly induced in liver macrophages from human subjects developing liver fibrosis from nonalcoholic fatty liver disease or hepatitis C virus infection. Furthermore, IRF5 expression positively correlated with clinical markers of liver damage, such as plasma transaminase and bilirubin levels. Interestingly, mice lacking IRF5 in myeloid cells (MKO) were protected from hepatic fibrosis induced by metabolic or toxic stresses. Transcriptional reprogramming of macrophages lacking IRF5 was characterized by immunosuppressive and antiapoptotic properties. Consequently, IRF5 MKO mice respond to hepatocellular stress by promoting hepatocyte survival, leading to complete protection from hepatic fibrogenesis. Our findings reveal a regulatory network, governed by IRF5, that mediates hepatocyte death and liver fibrosis in mice and humans. Therefore, modulating IRF5 function may be an attractive approach to experimental therapeutics in fibroinflammatory liver disease

Archives « secrètes » , secrets d’archives ?

En 1941, l’historien médiéviste Marc Bloch critiquait fermement dans l’Apologie pour l’histoire un obstacle à la connaissance historique, la “ passion du secret ”. Aujourd’hui, à l’heure où la “ transparence ” devient un lieu commun du discours public sur l’État et sur les pratiques politiques, cette passion française ne semble pas avoir complètement disparu. La soif actuelle d’histoire contemporaine et, particulièrement, d’histoire du “ temps présent ”, l’écho médiatique parfois juridique de certains débats historiques, ont fait de l’accès aux archives - question apparemment professionnelle, voire corporatiste - un enjeu public. Dans quelles conditions archivistes et historiens peuvent-ils exercer leurs métiers ? Au carrefour du droit des archives, du droit à l’information et du travail nécessairement critique de l’historien, les auteurs dialoguent et s’interrogent sur l’utilisation des archives sensibles. Bousculant les préjugés et les idées reçues, les contributions montrent l’importance d’une interrogation commune et publique sur les archives afin de permettre l’écriture de l’histoire aujourd’hui mais aussi préparer celle de demain. L’État contemporain, son attitude à l’égard des archives, son aptitude à permettre l’écriture de l’histoire, est ici au cœur d’un débat d’essence civique. L’infléchissement de la recherche universitaire face aux sources léguées par le passé, la découverte de nouveaux gisements d’archives amènent également les historiens à rechercher des approches nouvelles, à proposer des études originales afin de contribuer au progrès général de la connaissance