Research Interests:
The CBFβ gene encodes a transcription factor that, in combination with CBFα (also called Runx, runt-related transcription factor) regulates expression of several target genes. CBFβ interacts with all Runx family members, such as RUNX2, a... more
The CBFβ gene encodes a transcription factor that, in combination with CBFα (also called Runx, runt-related transcription factor) regulates expression of several target genes. CBFβ interacts with all Runx family members, such as RUNX2, a regulator of bone-related gene transcription that contains a conserved DNA-binding domain. CBFβ stimulates DNA binding of the Runt domain, and is essential for most of the known functions of RUNX2. A comparative analysis of the zebrafish cbfβ gene and protein, and of its orthologous identified homologous proteins in different species indicates a highly conserved function. We cloned eleven zebrafish cbfβ gene transcripts, one resulting in the known Cbfβ protein (with 187 aa), and three additional variants resulting from skipping exon 5a (resulting in a protein with 174 aa) or exon 5b (resulting in a protein with 201 aa), both observed for the first time in zebrafish, and a completely novel isoform containing both exon 5a and 5b (resulting in a protei...
Research Interests: Functional Analysis, Biology, Medicine, Sequence alignment, Animals, and 14 moreAlternative splicing, Gene, Transcription Factor, Molecular cloning, Zebrafish, Alternative Splicing, Protein isoforms, Amino Acid Sequence, Chromosomes, Exon, Protein Biosynthesis, Biochemistry and cell biology, Molecular Sequence Data, and conserved sequence
Identifying novel players of the pluripotency gene regulatory network centered on Oct4, Sox2, and Nanog as well as delineating the interactions within the complex network is key to understanding self-renewal and early cell fate commitment... more
Identifying novel players of the pluripotency gene regulatory network centered on Oct4, Sox2, and Nanog as well as delineating the interactions within the complex network is key to understanding self-renewal and early cell fate commitment of embryonic stem cells (ESC). While overexpression of the transcriptional regulator Cited2 sustains ESC pluripotency, its role in ESC functions remains unclear. Here, we show that Cited2 is important for proliferation, survival, and self-renewal of mouse ESC. We position Cited2 within the pluripotency gene regulatory network by defining Nanog, Tbx3, and Klf4 as its direct targets. We also demonstrate that the defects caused by Cited2 depletion are, at least in part, rescued by Nanog constitutive expression. Finally, we demonstrate that Cited2 is required for and enhances reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells. Stem Cells 2015;33:699–712
Research Interests: Biology, Cell Biology, Medicine, Heterogeneity, Biological Sciences, and 15 moreCell Differentiation, Humans, Pluripotency, Mice, Animals, Embryonic Stem Cell, Heart Development, Embryonic Stem Cells, Gene, Gene Regulatory Networks, Deficiency, Cell Proliferation, Cited, Pluripotent Stem Cells, and Medical and Health Sciences
The interaction of hypoxia-inducible factor 1α and the CH1 domain of the transcriptional coactivator p300/CBP is necessary for the expression of hypoxia responsive genes and tumor angiogenesis. The transcription factor CITED2 binds... more
The interaction of hypoxia-inducible factor 1α and the CH1 domain of the transcriptional coactivator p300/CBP is necessary for the expression of hypoxia responsive genes and tumor angiogenesis. The transcription factor CITED2 binds p300/CBP at the CH1 domain and functions as a negative regulator of hypoxia signaling by competing with hypoxia-inducible factor 1α. CITED4, a recently identified member of the CITED family, binds p300/CBP via the CH1 domain and functions as a coactivator for transcription factor AP-2. Here, we show that CITED4 blocks the binding of hypoxia-inducible factor 1α to p300 in vitro and inhibits hypoxia-inducible factor-1α transactivation and hypoxia-mediated reporter gene activation. These studies suggest that CITED4 might function as an inhibitor of hypoxia-inducible factor 1α. To explore the function of CITED4 in breast cancer, we determined its expression in normal, in situ and invasive breast cancers. We also correlated its expression in 286 invasive breas...
Research Interests: Cancer, Breast Cancer, Biology, Hypoxia, Medicine, and 15 moreGene expression, Estrogen Receptor, Transcription, Humans, Female, Monoclonal Antibodies, Transcription Factor, Middle Aged, Epidermal Growth Factor Receptor, Amino Acid Sequence, Cytoplasm, Nuclear Localization, Molecular Sequence Data, Hypoxia inducible factor, and Breast Neoplasms
Neurogenic niches constitute a powerful endogenous source of new neurons that can be used for brain repair strategies. Neuronal differentiation of these cells can be regulated by molecules such as retinoic acid (RA) or by mild levels of... more
Neurogenic niches constitute a powerful endogenous source of new neurons that can be used for brain repair strategies. Neuronal differentiation of these cells can be regulated by molecules such as retinoic acid (RA) or by mild levels of reactive oxygen species (ROS) that are also known to upregulate RA receptor alpha (RARα) levels. Data showed that neural stem cells from the subventricular zone (SVZ) exposed to blue light (405nm laser) transiently induced NADPH oxidase-dependent ROS, resulting in β-catenin activation and neuronal differentiation, and increased RARα levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR-NP). The synergy between blue light and LR-NP led to amplified neurogenesis both in vitro and in vivo, while offering a temporal and spatial control of RA release. In conclusion, this combinatory treatment offers great advantages to potentiate neuronal differentiation, and provides an i...
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Transcription of the murine interferon-A4 (IFN-A4) gene is mediated by a virus responsive element (VRE-A4) located in the promoter proximal [-120 to -43] region. VRE-A4 contains four DNA modules (A to D) which cooperate for maximal IFN-A4... more
Transcription of the murine interferon-A4 (IFN-A4) gene is mediated by a virus responsive element (VRE-A4) located in the promoter proximal [-120 to -43] region. VRE-A4 contains four DNA modules (A to D) which cooperate for maximal IFN-A4 activation following virus infection. The differential expression between the highly expressed IFN-A4 and the weakly inducible IFN-A11 gene promoters is essentially due to point mutations within the C and D modules of the virus-responsive element VRE-A11. We now demonstrate that in murine L929 and human 293 cells, transcription factors IRF-3 and IRF-7, which are potent activators of virus-induced type I IFN transcription, differentially affect IFN-A4 and IFN-A11 promoter activities. Using electrophoretic mobility shift assays and DNase I footprinting data, our studies demonstrate that the AB modules correspond to a preferential site for IRF-7, whereas the C module is preferentially recognized by IRF-3. Furthermore, transfection of reporter constructs driven by four copies of different GAAANN hexameric motifs found within VRE-A4 indicates that the NN residues of these hexameric sequences define the preferential binding sites for IRF-3 or IRF-7. Together, these experiments clarify the molecular basis for differential expression of IFN-A genes following virus infection by delineating the sequence requirements for IRF association with the virus responsive elements of the IFN-A genes.
Research Interests: Molecular Biology, Gene regulation, Transcription Factors, Cell line, Humans, and 15 moreMutation, Mice, Animals, Base Sequence, DNA binding proteins, Binding Site, DNA-footprinting, Response Elements, Biochemistry and cell biology, Gene Expression Regulation, Interferon Alpha, Molecular Sequence Data, binding sites, Interferon Regulatory FACTOR-1, and Interferon regulatory factors
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Transcriptomic data have become a fundamental resource for stem cell (SC) biologists as well as for a wider research audience studying SC-related processes such as aging, embryonic development and prevalent diseases including cancer,... more
Transcriptomic data have become a fundamental resource for stem cell (SC) biologists as well as for a wider research audience studying SC-related processes such as aging, embryonic development and prevalent diseases including cancer, diabetes and neurodegenerative diseases. Access and analysis of the growing amount of freely available transcriptomics datasets for SCs, however, are not trivial tasks. Here, we present StemMapper, a manually curated gene expression database and comprehensive resource for SC research, built on integrated data for different lineages of human and mouse SCs. It is based on careful selection, standardized processing and stringent quality control of relevant transcriptomics datasets to minimize artefacts, and includes currently over 960 transcriptomes covering a broad range of SC types. Each of the integrated datasets was individually inspected and manually curated. StemMapper's user-friendly interface enables fast querying, comparison, and interactive v...
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Seventeen pregnant ewes were orally fed variable amounts of either green or dried leaves of Ateleia glazioviana in 1 through 24 daily doses. All 17 ewes manifested some form of reproductive failure. Nine (52.9%) aborted their fetuses at 4... more
Seventeen pregnant ewes were orally fed variable amounts of either green or dried leaves of Ateleia glazioviana in 1 through 24 daily doses. All 17 ewes manifested some form of reproductive failure. Nine (52.9%) aborted their fetuses at 4 through 36 d after starting being fed the leaves of the plant; 1 had a stillbirth and in another 1 intrauterine fetal death was diagnosed. The other 6 ewes delivered 8 weak lambs, 7 of which died from few min to 48 h after birth. Three ewes had neurologic disturbances and loss of weight. Thirteen ewes were euthanatized 1-48 h after lambing or pregnancy loss; 2 of them had gross and histopathological changes related to the A glazioviana. Gross and histopathological changes observed in 7 lambs and in a stillborn, and histopathological changes found in 4 aborted fetuses from A glazioviana-fed ewes, were similar to those found in spontaneous poisoning by A glazioviana in adult cattle. It is concluded that A glazioviana has a powerful abortifacient activity whether ingested green or dried. The abortions caused by A glazioviana were not due to placental damage, but rather to transplacental induced fetal lesions consisting of toxic cardiomyopathy and spongy degeneration of the white matter of the brain. Fetuses succumbing to these lesions were expelled from the uterus; those not lethally affected are born weak with meager chances to survive.
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In vertebrates, stem cells play a fundamental role in embryogenesis and lifetime homeostasis of adult tissues. The transcriptional regulator Cited2 is essential for many mouse developmental and morphological processes, and mutations in... more
In vertebrates, stem cells play a fundamental role in embryogenesis and lifetime homeostasis of adult tissues. The transcriptional regulator Cited2 is essential for many mouse developmental and morphological processes, and mutations in human CITED2 gene have repeatedly been associated with congenital heart defects. An increasing number of studies have now described the importance of Cited2 in self-renewal and cell fate decision of embryonic stem cells (ESC) and some adult stem cells. Interestingly, the loss of stem cell properties due to aging or extensive regeneration of some adult stem cells has been associated with a decrease of Cited2 expression, while an aberrant increase in CITED2 expression might play a critical role in malignant oncologic processes. Here, we review recent advances unravelling the complexity of Cited2 function as a regulator of the maintenance and cell fate decision of ESC and adult stem cells, and present its potential role in pathological conditions by modu...
CITED2 is a ubiquitously expressed nuclear protein exhibiting a high affinity for the cysteine-histidine-rich domain 1 (CH1) of the transcriptional co-activators CBP/p300. CITED2 is particularly efficient in the inhibition of the... more
CITED2 is a ubiquitously expressed nuclear protein exhibiting a high affinity for the cysteine-histidine-rich domain 1 (CH1) of the transcriptional co-activators CBP/p300. CITED2 is particularly efficient in the inhibition of the hypoxia-inducible factor-1α (HIF-1α) dependent transcription by competing with it for the interaction with the CH1 domain. Here we report a direct and specific interaction between CITED2 and the F-box and leucine rich repeat protein 5 (FBXL5), a substrate adaptor protein which is part of E3 ubiquitin ligase complexes mediating protein degradation by the proteasome. We demonstrated that depletion of FBXL5 by RNA interference led to an increase of CITED2 protein levels. Conversely, overexpression of FBXL5 caused the decrease of CITED2 protein levels in a proteasome-dependent manner, and impaired the interaction between CITED2 and the CH1 domain of p300 in living cells. In undifferentiated mouse embryonic stem cells, the overexpression of FBXL5 also reduced Cited2 protein levels. Finally, we evidenced that FBXL5 overexpression and the consequent degradation of CITED2 enabled the transcriptional activity of the N-terminal transactivation domain of HIF-1α. Collectively, our results highlighted a novel molecular interaction between CITED2 and FBXL5, which might regulate the steady state CITED2 protein levels and contribute to the modulation of gene expression by HIF-1α.
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Comparative transfection analysis of murine interferon A4 and interferon A11 promoter constructs transiently transfected in mouse L929 and human HeLa S3 cells infected with Newcastle disease virus showed that the second positive... more
Comparative transfection analysis of murine interferon A4 and interferon A11 promoter constructs transiently transfected in mouse L929 and human HeLa S3 cells infected with Newcastle disease virus showed that the second positive regulatory domain I-like domain (D motif), located between nucleotides -57 and -46 upstream of the transcription start site, contributes to the activation of virus-induced transcription of the interferon (IFN)-A4 gene promoter by cooperating with the positive regulatory domain I-like and TG-like domains previously described. Electrophoretic mobility shift assay performed with the virus-inducible fragments containing these motifs indicated that the binding activity that we have denoted as virus-induced factor (Génin, P., Bragança, J., Darracq, N., Doly, J., and Civas, A. (1995) Nucleic Acids Res. 23, 5055-5063) is different from interferon-stimulated gene factor 3. It binds to the D motif but not to the virus-unresponsive form of the D motif disrupted by a G-57 --> C substitution. We show that the low levels of IFN-A11 gene expression are caused essentially by the lack of two inducible enhancer domains disrupted by the A-78 --> G and the G-57 --> C substitutions. These data suggest a model taking account of the differential regulation of IFN-A gene family members. They also suggest that virus-induced factor may correspond to the primary transcription factor directly activated by virus that is involved in the initiation of IFN-A gene transcription.
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The transcriptional co-activators and histone acetyltransferases p300/CREB-binding protein (CBP) interact with CITED2, a transcription factor AP-2 (TFAP2) co-activator. p300/CBP, CITED2, and TFAP2A are essential for normal neural tube and... more
The transcriptional co-activators and histone acetyltransferases p300/CREB-binding protein (CBP) interact with CITED2, a transcription factor AP-2 (TFAP2) co-activator. p300/CBP, CITED2, and TFAP2A are essential for normal neural tube and cardiac development. Here we show that p300 and CBP co-activate TFAP2A in the presence of CITED2. TFAP2A transcriptional activity was modestly impaired in p300(+/-) and CBP(+/-) mouse embryonic fibroblasts; this was rescued by ectopic expression of p300/CBP. p300, TFAP2A, and endogenous CITED2 could be co-immunoprecipitated from transfected U2-OS cells indicating that they can interact physically in vivo. CITED2 interacted with the dimerization domain of TFAP2C, which is highly conserved in TFAP2A/B. In mammalian two-hybrid experiments, full-length p300 and TFAP2A interacted only when CITED2 was co-transfected. N-terminal residues of TFAP2A, containing the transactivation domain, are both necessary and sufficient for interaction with p300, and this...
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IntroductionMyocardial development is dependent on the concomitant growth of cardiomyocytes and a supporting vascular network. The coupling of myocardial and coronary vascular development is mediated in part by VEGFA signalling. Cited2 is... more
IntroductionMyocardial development is dependent on the concomitant growth of cardiomyocytes and a supporting vascular network. The coupling of myocardial and coronary vascular development is mediated in part by VEGFA signalling. Cited2 is a transcriptional co-factor that can inhibit hypoxia-activated transcription and also acts as a co-activator for transcription factors such as TFAP2. Genetic evidence indicates that Cited2 is essential for
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The family of interferon regulatory transcription factors (IRF) participates in the virus-induced and dsRNA-stimulated transcriptional regulation of either type I IFN genes or a definite set of genes which can also be activated by IFN. In... more
The family of interferon regulatory transcription factors (IRF) participates in the virus-induced and dsRNA-stimulated transcriptional regulation of either type I IFN genes or a definite set of genes which can also be activated by IFN. In this review, we place emphasis on the role of IRF-3 that associates with the coactivators CBP and/or p300, together or not with IRF-7. These
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Stem cells are characterized by their potential for self-renewal and their capacity to differentiate into mature cells. These two key features emerge through the interplay of various factors within complex molecular networks. To provide... more
Stem cells are characterized by their potential for self-renewal and their capacity to differentiate into mature cells. These two key features emerge through the interplay of various factors within complex molecular networks. To provide researchers with a dedicated tool to investigate these networks, we have developed StemCellNet, a versatile web server for interactive network analysis and visualization. It rapidly generates focused networks based on a large collection of physical and regulatory interactions identified in human and murine stem cells. The StemCellNet web-interface has various easy-to-use tools for selection and prioritization of network components, as well as for integration of expression data provided by the user. As a unique feature, the networks generated can be screened against a compendium of stemness-associated genes. StemCellNet can also indicate novel candidate genes by evaluating their connectivity patterns. Finally, an optional dataset of generic interactio...
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Research Interests: Engineering, Physics, Chemistry, Biology, Medicine, and 16 moreMultidisciplinary, Congenital Heart Defects, Humans, Mutation, Mice, Animals, Phosphorylation, Embryonic Stem Cells, Mitogen Activated Protein Kinase, PLoS one, Cell Proliferation, Amino Acid Sequence, Amino Acid Substitution Rates, Structure activity Relationship, Leukemia Inhibitory Factor, and Case Control Studies
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Research Interests:
Transcription of the murine interferon-A4 (IFN-A4) gene is mediated by a virus responsive element (VRE-A4) located in the promoter proximal [-120 to -43] region. VRE-A4 contains four DNA modules (A to D) which cooperate for maximal IFN-A4... more
Transcription of the murine interferon-A4 (IFN-A4) gene is mediated by a virus responsive element (VRE-A4) located in the promoter proximal [-120 to -43] region. VRE-A4 contains four DNA modules (A to D) which cooperate for maximal IFN-A4 activation following virus infection. The differential expression between the highly expressed IFN-A4 and the weakly inducible IFN-A11 gene promoters is essentially due to point mutations within the C and D modules of the virus-responsive element VRE-A11. We now demonstrate that in murine L929 and human 293 cells, transcription factors IRF-3 and IRF-7, which are potent activators of virus-induced type I IFN transcription, differentially affect IFN-A4 and IFN-A11 promoter activities. Using electrophoretic mobility shift assays and DNase I footprinting data, our studies demonstrate that the AB modules correspond to a preferential site for IRF-7, whereas the C module is preferentially recognized by IRF-3. Furthermore, transfection of reporter constructs driven by four copies of different GAAANN hexameric motifs found within VRE-A4 indicates that the NN residues of these hexameric sequences define the preferential binding sites for IRF-3 or IRF-7. Together, these experiments clarify the molecular basis for differential expression of IFN-A genes following virus infection by delineating the sequence requirements for IRF association with the virus responsive elements of the IFN-A genes.
Research Interests:
Comparative transfection analysis of murine interferon A4 and interferon A11 promoter constructs transiently transfected in mouse L929 and human HeLa S3 cells infected with Newcastle disease virus showed that the second positive... more
Comparative transfection analysis of murine interferon A4 and interferon A11 promoter constructs transiently transfected in mouse L929 and human HeLa S3 cells infected with Newcastle disease virus showed that the second positive regulatory domain I-like domain (D motif), located between nucleotides -57 and -46 upstream of the transcription start site, contributes to the activation of virus-induced transcription of the interferon (IFN)-A4 gene promoter by cooperating with the positive regulatory domain I-like and TG-like domains previously described. Electrophoretic mobility shift assay performed with the virus-inducible fragments containing these motifs indicated that the binding activity that we have denoted as virus-induced factor (Génin, P., Bragança, J., Darracq, N., Doly, J., and Civas, A. (1995) Nucleic Acids Res. 23, 5055-5063) is different from interferon-stimulated gene factor 3. It binds to the D motif but not to the virus-unresponsive form of the D motif disrupted by a G-57 --> C substitution. We show that the low levels of IFN-A11 gene expression are caused essentially by the lack of two inducible enhancer domains disrupted by the A-78 --> G and the G-57 --> C substitutions. These data suggest a model taking account of the differential regulation of IFN-A gene family members. They also suggest that virus-induced factor may correspond to the primary transcription factor directly activated by virus that is involved in the initiation of IFN-A gene transcription.