Laboratoire d’accueil pour étudiants en M2R et doctorants en Science
Master 2 Recherche « Signalisation Cellulaire et Moléculaire », Université de Bourgogne-Franche-Comté, Dijon et Besançon
Master 2 Recherche « Biochimie, Cellules, Cibles Thérapeutiques », Université Paris-Diderot-Paris 7, Paris
Alteration of cross-talks involving a deregulation of hematopoietic transcription factors or co-regulators may affect the differentiation process and increase the capacity to generate leukemogenic abnormalities in hematopoietic cells.
The aim of our team is mainly to understand the transcription regulation by transcription co-regulators in a normal and tumoral hematopoietic environment.
The different topics of the team regard the study of gene regulation by transcription and post-transcriptional co-regulators such as TIF1gamma, cIAP1 and miR-142-3p.
TIF1g (Transcription Intermediary Factor 1 gamma, also called TRIM33) located at 1p13.1, encodes for an E3 ubiquitin ligase, as CBL, which belongs to the TRIM (tripartite motif) family. Four TIF1 members (alpha to delta) have been identified in mammals, and orthologs are present in organisms such as Drosophila.
TIF1g interacts with nuclear receptors and modulates their transcriptional activity either positively or negatively in a ligand-dependent fashion. In mice, TIF1g functions as a liver-specific tumor suppressor whose deletion reveals the deleterious effect of retinoic acid receptor alpha aberrant activation to liver homeostasis.
TIF1b, a component of the histone deacetylase N-CoR1/HDAC3 complex, functions as a co-repressor for the large family of Krüppel-associated box (KRAB) zinc-finger transcription factors, and is required for post-implantation embryogenesis and mesoderm induction. TIF1g is involved in heterochromatin-mediated gene silencing.
Mutations in the zebrafish mon (tif1g) gene cause a disruption in both primitive embryonic and definitive adult hematopoiesis, resulting in a severe loss of erythroid cells. In zebrafish and human stem/progenitor CD34+ cells, TIF1g functionally links positive elongation factors to blood specific transcription complexes to regulate the erythroid commitment. We have identified TIF1g as a tumor suppressor in murine hematopoietic cells (Aucagne et al., 2011). Interestingly, we also found that in mice, specific deletion of the Tif1g gene in the hematopoietic cells induced an age-dependent myeloproliferative disorder that mimicked some of the essential features of human chronic myelomonocytic leukemia (CMML).
In CMML patients, TIF1g level is very low and almost undetectable in leukemic cells of more than 35% of patients. TIF1g decreased expression is not due to gene mutation but to the gene promoter hypermethylation. We are investigating the role of Tif1g in murine hematopoiesis by using a hematopoietic specific targeted mouse model.
IAPs (inhibitors of apoptosis) constitute an evolutionary conserved family of proteins, discovered in baculovirus as potent inhibitors of apoptosis in infected insect cells (Gyrd-Hansen et al. Nat. Rev. 2010).
Beside apoptosis regulation, most of them also display non-apoptotic functions in innate immunity, inflammatory response, cell proliferation, cell division and cell motility. Human genome encodes 8 IAPs including NAIP (neuronal apoptosis-inhibitory protein), cIAP1 (cellular IAP1), cIAP2, XIAP (X-linked IAP), ILP2 (IAP-like protein-2), ML-IAP (melanoma IAP)/Livin, and survivin. Among IAPs, cIAP1 is an E3-ubiquitin ligase with oncogenic properties.
cIAP1 It is highly expressed in number of cancer samples and its expression has been correlated with poor prognosis or low response to anti-cancer therapy (Fulda et al. Nat. Rev. Drug Discovery 2012). is an important regulator of the signaling pathways activated by the Tumor Necrosis Factor (TNF) receptor superfamily members and modulates NF-κB activation.
We have shown that cIAP1 is expressed mainly in the nucleus of undifferentiated, proliferating cells and was excluded upon cell differentiation (Plenchette et al. Blood 2004, Didelot et al. Cell Death Diff 2008, Dupoux et al. Blood 2009).
cIAP1 is also detected in the nucleus of primary human tumor cells (Cartier et al. J. Biol. Chem. 2011) and the nuclear expression of cIAP1 has been associated with advanced disease stages suggesting that the nuclear function of cIAP1 could account for its oncogenic properties. The nuclear function of cIAP1 remained misunderstood.
Our goals were to identify the nuclear functions of cIAP1 and to determine the importance of these functions in oncogenic activity of cIAP1. We identified a new function of cIAP1 in the control of the activity of E2F1 transcription factor (Cartier et al. J. Biol. Chem 2011).
Human peripheral blood monocytes are seminal effectors and regulators of the host inflammatory and innate immune responses. They are produced in the bone marrow, circulate in the blood, and enter into tissues under inflammatory conditions to give rise to a variety of macrophages and inflammatory dendritic cells, depending on their environment. Ex vivo exposure of monocytes to Colony-Stimulating Factor 1 (CSF1), also known as Macrophage-Colony Stimulating Factor (M-CSF), induces their differentiation into macrophages.
We identified the contribution of miR-142-3p to CSF1-induced differentiation of human monocytes and demonstrated that this miRNA is part of a molecular circuitry that also involves the transcription factor EGR2 (Lagrange et al., 2013). The decreased expression of miR-142-3p in the monocytes of the most proliferative chronic myelomonocytic leukemic patients enforces the demonstration that these leukemic monocytes are dysplastic with altered differentiation capabilities.
We are investigating the role of miR-142-3p in hematopoiesis.