Fonctions de l'oncoprotéine LMO2 déterminées par ses interactions protéiques

La leucémie lymphoïde représente environ 30% des cas de cancer chez l’enfant. Elle est souvent causée par des réarrangements chromosomiques impliquant des gènes encodant des facteurs de transcription, qui contrôlent des programmes génétiques complexes. Par exemple, LMO2 (LIM-only 2) est un facteur de transcription oncogénique fréquemment exprimé de façon aberrante dans les leucémies lymphoblastiques aigues des cellules T (T-ALL). Dans l’hématopoïèse normale, LMO2 est essentiel à la génération des cellules souches hématopoïétiques à l’origine de toutes les cellules sanguines. D’ailleurs, certaines cellules leucémiques possèdent des propriétés normalement réservées aux cellules souches hématopoïétiques. Ainsi, l’étude de la fonction de LMO2 dans les cellules souches hématopoïétiques peut être pertinente autant dans le contexte hématopoïétique normal que leucémique. Afin de mettre en évidence de nouvelles fonctions moléculaires pour LMO2, j’ai choisi d’identifier les protéines qui s’y associent. En plus de ses partenaires connus, j’ai identifié plusieurs protéines de transcription/remodelage de la chromatine, en accord avec son rôle transcriptionnel. Plusieurs nouvelles fonctions potentielles ont été révélées, indiquant que cette protéine adaptatrice pourrait faire partie de complexes non transcriptionnels, régulant d’autres processus cellulaires. Les oncogènes comme LMO2 pourraient être des régulateurs à large spectre. Particulièrement, j’ai identifié des interactions entre LMO2 et des protéines de réplication de l’ADN. J’ai montré que LMO2 contrôle la réplication de l’ADN dans les cellules hématopoïétiques, et possiblement durant la leucémogenèse, indépendamment de son rôle transcriptionnel. Ensemble, ces études ont donc permis de révéler de nouvelles fonctions pour LMO2, et pourraient servir de paradigme pour d’autres facteurs de transcription oncogéniques, particulièrement aux autres protéines de la famille LMO, qui sont aussi des oncogènes puissants.Lymphoid leukemia represents about 30% of childhood cancer cases. It is often caused by chromosomal rearrangements involving genes coding for transcription factors, controlling complex genetic programs. As an example, the oncogenic transcription factor LMO2 (LIM-only 2) is often aberrantly expressed in T cell acute lymphoblastic leukemia (T-ALL). In normal hematopoiesis, LMO2 is essential for the generation of hematopoietic stem cells that give rise to all blood cells. Moreover, some leukemic cells possess properties normally reserved to hematopoietic stem cells. Thus, studying the role of LMO2 in hematopoietic stem cells could be relevant to the contexts of normal hematopoiesis and leukemogenesis. To reveal new molecular functions for LMO2, I chose to identify its associated proteins. In addition to its known protein partners, I identified many proteins involved in transcription/chromatin remodeling, in agreement with its transcriptional role. In addition, several new potential functions have been revealed, indicating that this scaffold protein could be part of non-transcriptional protein complexes, regulating different cell processes. Oncogenes like LMO2 could be master regulators in normal hematopoietic and leukemic cells. Particularly, I identified protein-protein interactions between LMO2 and DNA replication proteins. I demonstrated that LMO2 controls S phase progression in hematopoietic cells, independently of its association in transcriptional complexes. LMO2 overexpression in mice induces T-ALL and affects specifically the cell cycle status of thymocyte progenitors, which are targets of transformation by LMO2. Thus, LMO2 promotes DNA replication in hematopoietic cells, and possibly in leukemogenesis. Together, these studies allowed to reveal new functions for LMO2, and could serve as a paradigm for other oncogenic transcription factors, especially for other LMO proteins which are all potent oncogenes

Des liens entre métabolisme et régulation épigénétique des cellules souches musculaires = Emerging links between metabolism and epigenetic regulation of muscle stem cells

Résumé La régénération musculaire dépend de la capacité des cellules souches musculaires, aussi appelées cellules satellites, à proliférer et à se différencier pour réparer les muscles endommagés. En l’absence de dommage, ces cellules sont quiescentes : elles ne prolifèrent pas et présentent un métabolisme réduit. Des études récentes ont révélé l’existence de liens entre la régulation épigénétique et le métabolisme des cellules souches musculaires. Dans cette synthèse, nous discutons les modifications épigénétiques des histones et les voies métaboliques qui ont été observées dans les cellules souches musculaires quiescentes et qui sont à l’origine de leur activation en réponse à une blessure. Abstract Muscle regeneration in response to injury or exercise relies on the ability of muscle stem cells to proliferate and differentiate to repair the damage. In the absence of damage, muscle stem cells are quiescent: they do not proliferate and have a very low metabolism. Recent studies have linked the metabolic state of the adult muscle stem cell to its epigenetic regulation. This article synthesizes the known concepts about histone modifications and metabolic pathways found in quiescent muscle stem cells, as well as the metabolic and epigenetic changes leading to muscle stem cell activation in response to injury. Here, we discuss the heterogeneity in quiescent stem cell metabolism and compare the metabolism of quiescent and activated muscle stem cells, and describe the epigenetic changes related to their activation. We also discuss the involvement of SIRT1, an important effector of muscle stem cells metabolism, together with the effects of aging and caloric restriction

Modeling Variable Linear Polarization Produced by Co-Rotating Interaction Regions (CIRs) Across Optical Recombination Lines of Wolf-Rayet Stars

Massive star winds are structured both stochastically ("clumps") and often coherently (Co-rotation Interaction Regions, or CIRs). Evidence for CIRs threading the winds of Wolf-Rayet (WR) stars arises from multiple diagnostics including linear polarimetry. Some observations indicate changes in polarization position angle across optical recombination emission lines from a WR star wind but limited to blueshifted Doppler velocities. We explore a model involving a spherical wind with a single conical CIR stemming from a rotating star as qualitative proof-of-concept. To obtain a realistic distribution of limb polarization and limb darkening across the pseudo-photosphere formed in the optically thick wind of a WR star, we used Monte Carlo radiative transfer (MCRT). Results are shown for a parameter study. For line properties similar to WR 6 (EZ CMa; HD 50896), the combination of the MCRT results, a simple model for the CIR, and the Sobolev approximation for the line formation, we were able to reproduce variations in both polarization amplitude and position angle commensurate with observations. Characterizing CIRs in WR~winds has added importance for providing stellar rotation periods since the v sin i values are unobtainable because the pseudo-photosphere forms in the wind itself.Comment: This is a pre-copyedited, author-produced PDF of an article accepted for publication in MNRAS following peer revie

Dynamic Phosphorylation of the Myocyte Enhancer Factor 2C alpha 1 Splice Variant Promotes Skeletal Muscle Regeneration and Hypertrophy

AFM Research. Grant Numbers: 18364, 16252 Optistem (European collaborative project HEALTH-2007-1.4-6) Fondazione Roma, Telethon ASI Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ) Heidelberg University, Heidelberg, Germany Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdo

Goal Oriented Execution for LOTOS Mazen

The dynamic semantics of LOTOS are defined in terms of axioms and inference rules which generate, from a given behaviour expression, the next possible actions and their resulting behaviour expressions. In this paper, we present a new type of inference rules, which are capable of generating traces of actions leading to a pre-selected action in the specification. These inference rules are guided by the static derivation path of the pre-selected action, which locates the action in the abstract syntactic tree of the current behaviour statically. This allows a considerable reduction of the search space. Such a technique often permits the analysis of divergent specifications that are generally beyond the capabilities of verification tools based on traces

Interactive Conflict Detection and Resolution for Personalized Features

Abstract: In future telecommunications systems, behaviour will be defined by inexperienced users for many different purposes, often by specifying requirements in the form of policies. The Call Processing Language (CPL) was developed by the IETF in order to make it possible to define telephony policies in an Internet telephony environment. However, user-defined policies can hide inconsistencies or feature interactions. In this paper, a method and a tool are proposed to flag inconsistencies in a set of policies and to assist the user in correcting them. These policies can be defined by the user in a user-friendly language or derived automatically from a CPL script. The approach builds on a pre-existing logic programming tool that is able to identify inconsistencies in feature definitions. Our new tool is capable of explaining in user-oriented terminology the inconsistencies flagged, to suggest possible solutions, and to implement the chosen solution. It is sensitive to the types of features and interactions that will be created by naive users. This tool is also capable of assembling a set of individual policies specified in a user-friendly manner into a single CPL script in an appropriate priority order for execution by telecommunication systems