Irwin Davidson

University of Strasbourg, Strasburg, Alsace, France

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Publications (134)1068.84 Total impact

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    ABSTRACT: There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ(+)CD4(+) T-helper 2 (TH2) cells orchestrate the type-2-driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081-E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4(gfp+)αβ(+)CD4(+) TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell-intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24(-/-) T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1-regulated signaling. Following this prediction, we found that Trim24(-/-) T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β-mediated activation in vitro and in vivo, and fail to respond to IL-1β-exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell-intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.
    No preview · Article · Jan 2016 · Proceedings of the National Academy of Sciences

  • No preview · Article · Dec 2015 · Nature
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    ABSTRACT: Inflammation promotes phenotypic plasticity in melanoma, a source of non-genetic hetero-geneity, but the molecular framework is poorly understood. Here we use functional genomic approaches and identify a reciprocal antagonism between the melanocyte lineage transcription factor MITF and c-Jun, which interconnects inflammation-induced dedifferentiation with pro-inflammatory cytokine responsiveness of melanoma cells favouring myeloid cell recruitment. We show that pro-inflammatory cytokines such as TNF-a instigate gradual suppression of MITF expression through c-Jun. MITF itself binds to the c-Jun regulatory genomic region and its reduction increases c-Jun expression that in turn amplifies TNF-stimulated cytokine expression with further MITF suppression. This feed-forward mechanism turns poor peak-like transcriptional responses to TNF-a into progressive and persistent cytokine and chemokine induction. Consistently, inflammatory MITF low /c-Jun high syngeneic mouse melanomas recruit myeloid immune cells into the tumour microenviron-ment as recapitulated by their human counterparts. Our study suggests myeloid cell-directed therapies may be useful for MITF low /c-Jun high melanomas to counteract their growth-promoting and immunosuppressive functions.
    Full-text · Article · Nov 2015 · Nature Communications
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    ABSTRACT: MIcrophthalmia-associated Transcription Factor (MITF) regulates melanocyte and melanoma physiology. We show that MITF associates the NURF chromatin-remodelling factor in melanoma cells. ShRNA-mediated silencing of the NURF subunit BPTF revealed its essential role in several melanoma cell lines and in untransformed melanocytes in vitro. Comparative RNA-seq shows that MITF and BPTF co-regulate overlapping gene expression programs in cell lines in vitro. Somatic and specific inactivation of Bptf in developing murine melanoblasts in vivo shows that Bptf regulates their proliferation, migration and morphology. Once born, Bptf-mutant mice display premature greying where the second post-natal coat is white. This second coat is normally pigmented by differentiated melanocytes derived from the adult melanocyte stem cell (MSC) population that is stimulated to proliferate and differentiate at anagen. An MSC population is established and maintained throughout the life of the Bptf-mutant mice, but these MSCs are abnormal and at anagen, give rise to reduced numbers of transient amplifying cells (TACs) that do not express melanocyte markers and fail to differentiate into mature melanin producing melanocytes. MSCs display a transcriptionally repressed chromatin state and Bptf is essential for reactivation of the melanocyte gene expression program at anagen, the subsequent normal proliferation of TACs and their differentiation into mature melanocytes.
    Full-text · Article · Oct 2015 · PLoS Genetics
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    ABSTRACT: All-trans retinoic acid (ATRA) is instrumental to male germ cell differentiation, but its mechanism of action remains elusive. To address this question, we have analyzed the phenotypes of mice lacking, in spermatogonia, all rexinoid receptors (RXRA, RXRB and RXRG) or all ATRA receptors (RARA, RARB and RARG). We demonstrate that the combined ablation of RXRA and RXRB in spermatogonia recapitulates the set of defects observed both upon ablation of RAR in spermatogonia. We also show that ATRA activates RAR and RXR bound to a conserved regulatory region to increase expression of the SALL4A transcription factor in spermatogonia. Our results reveal that this major pluripotency gene is a target of ATRA signaling and that RAR/RXR heterodimers are the functional units driving its expression in spermatogonia. They add to the mechanisms through which ATRA promote expression of the KIT tyrosine kinase receptor to trigger a critical step in spermatogonia differentiation. Importantly, they indicate also that meiosis eventually occurs in the absence of a RAR/RXR pathway within germ cells and suggest that instructing this process is either ATRA-independent or requires an ATRA signal originating from Sertoli cells.
    Full-text · Article · Oct 2015 · PLoS Genetics
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    ABSTRACT: The multifunctional Ig-like carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is neo-expressed in the majority of malignant melanoma lesions. CEACAM1 acts as a driver of tumor cell invasion and its expression correlates with poor patient prognosis. Despite its importance in melanoma progression, how CEACAM1 expression is regulated is largely unknown. Here, we show that CEACAM1 expression in melanoma cell lines and melanoma tissue strongly correlates with that of the microphthalmia-associated transcription factor (MITF), a key regulator of melanoma proliferation and invasiveness. MITF is revealed as a direct and positive regulator for CEACAM1 expression via binding to an M-box motif located in the CEACAM1 promoter. Taken together, our study provides novel insights into the regulation of CEACAM1 expression and suggests an MITF-CEACAM1 axis as a potential determinant of melanoma progression. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Aug 2015 · Pigment Cell & Melanoma Research

  • No preview · Article · Aug 2015 · Cancer Research
  • Sylvia Urban · Tao Ye · Irwin Davidson

    No preview · Chapter · Jun 2015
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    ABSTRACT: Murine embryonic stem (ES) cells treated with all-trans retinoic acid (RA) differentiate into a homogenous population of glutamatergic neurons. While differentiation is initiated by activation of target genes by the RA-receptors, the downstream transcription factors specifying neuronal fate are less well characterised. We show that transcription factor Pou3f2 (Brn2) is essential for the neuronal differentiation programme. By integrating RNA-seq following Brn2 silencing with Brn2 ChIP-seq, we identify a set of Brn2 target genes required for the neurogenic programme. Further integration of Brn2 ChIP-seq data from RA-treated ES and P19 cells with ES cells differentiated into neuronal precursors by Fgf2 treatment and fibroblasts trans-differentiated into neurons by ectopic Brn2 expression showed Brn2 occupancy of a distinct but overlapping set of genomic loci. However, a set of common binding sites and target genes define the core of the Brn2-regulated neuronal program amongst which is transcription factor Zic1. ShRNA mediated silencing of Zic1 abrogates neural fate thus defining a hierarchical Brn2-Zic1 axis essential to specify the neural fate of RA-treated ES cells. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · May 2015 · Journal of Cell Science
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    ABSTRACT: Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. To understand how MITF regulates transcription, we used tandem affinity purification and mass spectrometry to define a comprehensive MITF interactome identifying novel cofactors involved in transcription, DNA replication and repair, and chromatin organisation. We show that MITF interacts with a PBAF chromatin remodelling complex comprising BRG1 and CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF-associated regulatory elements (MAREs) at active enhancers. Combinations of MITF, SOX10, TFAP2A, and YY1 bind between two BRG1-occupied nucleosomes thus defining both a signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of the regulatory elements they occupy. BRG1 also regulates the dynamics of MITF genomic occupancy. MITF-BRG1 interplay thus plays an essential role in transcription regulation in melanoma.
    Full-text · Article · Mar 2015 · eLife Sciences
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    ABSTRACT: Huntington's disease (HD) is a neurodegenerative disease associated with extensive down-regulation of genes controlling neuronal function, particularly in the striatum. Whether altered epigenetic regulation underlies transcriptional defects in HD is unclear. Integrating RNA-sequencing (RNA-seq) and chromatin-immunoprecipitation followed by massively parallel sequencing (ChIP-seq), we show that down-regulated genes in HD mouse striatum associate with selective decrease of H3K27ac, a mark of active enhancers, and RNA Polymerase II (RNAPII). In addition, we reveal that decreased genes in HD mouse striatum display a specific epigenetic signature, characterized by high levels and broad patterns of H3K27ac and RNAPII. Our results indicate that this signature is that of super-enhancers, a category of broad enhancers regulating genes defining tissue identity and function. Specifically, we reveal that striatal super-enhancers display extensive H3K27 acetylation within gene bodies, drive transcription characterized by low levels of paused RNAPII, regulate neuronal function genes and are enriched in binding motifs for Gata transcription factors, such as Gata2 regulating striatal identity genes. Together, our results provide evidence for preferential down-regulation of genes controlled by super-enhancers in HD striatum, and indicate that enhancer topography is a major parameter determining the propensity of a gene to be deregulated in a neurodegenerative disease. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    No preview · Article · Mar 2015 · Human Molecular Genetics
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    Dataset: SupSciRep

    Full-text · Dataset · Feb 2015
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    Benjamin Herquel · Céline Keime · Irwin Davidson

    Full-text · Article · Feb 2015 · Journal of Hepatology
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    ABSTRACT: Retinoid X receptors (RXRs) act as homodimers or heterodimerisation partners of class II nuclear receptors. RXR homo- and heterodimers bind direct repeats of the half-site (A/G)G(G/T)TCA separated by 1 nucleotide (DR1). We present a structural characterization of RXR-DNA binding domain (DBD) homodimers on several natural DR1s and an idealized symmetric DR1. Homodimers displayed asymmetric binding, with critical high-affinity interactions accounting for the 3' positioning of RXR in heterodimers on DR1s. Differing half-site and spacer DNA sequence induce changes in RXR-DBD homodimer conformation notably in the dimerization interface such that natural DR1s are bound with higher affinity than an idealized symmetric DR1. Subtle changes in the consensus DR1 DNA sequence therefore specify binding affinity through altered RXR-DBD-DNA contacts and changes in DBD conformation suggesting a general model whereby preferential half-site recognition determines polarity of heterodimer binding to response elements.
    Full-text · Article · Feb 2015 · Scientific Reports
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    Irwin Davidson · Dominique Kobi · Anas Fadloun · Gabrielle Mengus
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    ABSTRACT: RNA polymerase II general transcription factor TFIID is a macromolecular complex comprising the TATA-binding protein, TBP and 13-14 evolutionary conserved TBP-associated factors, TAFs. Although genetic experiments have shown that TAFs are essential for cell cycle progression in yeast and in rapidly proliferating vertebrate cells in vitro, new experiments indicate they may be dispensible in specific developmental and physiological processes. Moreover, the TAF4 subunit of TFIID negatively regulates proliferation by inhibiting activation of the TGFβ signalling pathway by its paralogue TAF4b. TAF4 is however essential in the retinoic acid and cAMP signalling pathways acting as a cofactor for CREB and the retinoic acid receptor, but is a negative regulator of the ATF7 transcription factor.
    Full-text · Article · Oct 2014 · Cell cycle (Georgetown, Tex.)
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    ABSTRACT: The functions of the TAF subunits of mammalian TFIID in physiological processes remain poorly characterised. In this study, we describe a novel function of TAFs in directing genomic occupancy of a transcriptional activator. Using liver-specific inactivation in mice, we show that the TAF4 subunit of TFIID is required for post-natal hepatocyte maturation. TAF4 promotes pre-initiation complex (PIC) formation at post-natal expressed liver function genes and down-regulates a subset of embryonic expressed genes by increased RNA polymerase II pausing. The TAF4–TAF12 heterodimer interacts directly with HNF4A and in vivo TAF4 is necessary to maintain HNF4A-directed embryonic gene expression at post-natal stages and promotes HNF4A occupancy of functional cis-regulatory elements adjacent to the transcription start sites of post-natal expressed genes. Stable HNF4A occupancy of these regulatory elements requires TAF4-dependent PIC formation highlighting that these are mutually dependent events. Local promoter-proximal HNF4A–TFIID interactions therefore act as instructive signals for post-natal hepatocyte differentiation. DOI: http://dx.doi.org/10.7554/eLife.03613.001
    Full-text · Article · Sep 2014 · eLife Sciences
  • K. Merienne · MA Jreda · C. Keime · S. Le Gras · I. Davidson
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    ABSTRACT: Transcriptional dysregulation is a central mechanism of Huntington’s disease (HD) pathogenesis. Gene expression changes are extensive, particularly in the striatum, but specific, defining a transcriptomic signature enriched in neuronal genes. Epigenetic mechanisms control transcription, suggesting that epigenetic alterations might contribute to HD transcriptional dysregulation. To address this question, we combined RNA-sequencing (RNA-seq) and chromatin-immunoprecipitation followed by massively parallel sequencing (ChIP-seq) on the striatum of HD R6/1 transgenic and control mice. ChIP-seq experiments were performed using antibodies to RNAPII and H3K27ac, a histone modification marking active enhancers. Integrated analysis of RNA-seq and ChIP-seq data shows that H3K27ac and RNAPII are specifically decreased at down-regulated genes in R6/1 striatum relative to controls. Further data analysis reveals that genes targeted for down-regulation in R6/1 striatum exhibit a specific RNAPII and H3K27ac signature. This signature defines neuronal genes and identifies genes with elevated levels of RNAPII at gene body relative to transcription start site (e.g. RNAPII non-paused genes). H3K27ac occupancy parallels that of RNAPII and is elevated and spread throughout the body of the genes exhibiting the signature, suggesting that the signature delineates genes regulated through super-enhancers. Together, our results indicate that striatal RNAPII non-paused genes are under control of super-enhancers, regulate neuronal genes and are preferentially down-regulated in HD striatum. We anticipate that specific targeting of RNAPII non-paused genes might be a promising therapeutic avenue for HD.
    No preview · Article · Sep 2014 · Journal of Neurology Neurosurgery & Psychiatry
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    ABSTRACT: It is well established that tumours are not homogenous, but comprise cells with differing invasive, proliferative and tumour-initiating potential. A major challenge in cancer research is therefore to develop methods to characterize cell heterogeneity. In melanoma, proliferative and invasive cells are characterized by distinct gene expression profiles and accumulating evidence suggests that cells can alternate between these states through a process called phenotype switching. We have used microfluidic technology to isolate single melanoma cells grown in vitro as monolayers or melanospheres or in vivo as xenografted tumours and analyse the expression profiles of 114 genes that discriminate the proliferative and invasive states by quantitative PCR. Single-cell analysis accurately recapitulates the specific gene expression programmes of melanoma cell lines and defines subpopulations with distinct expression profiles. Cell heterogeneity is augmented when cells are grown as spheres and as xenografted tumours. Correlative analysis identifies gene-regulatory networks and changes in gene expression under different growth conditions. In tumours, subpopulations of cells that express specific invasion and drug resistance markers can be identified amongst which is the pluripotency factor POUF51 (OCT4) whose expression correlates with the tumorigenic potential. We therefore show that single-cell analysis can be used to define and quantify tumour heterogeneity based on detection of cells with specific gene expression profiles.Oncogene advance online publication, 18 August 2014; doi:10.1038/onc.2014.262.
    Full-text · Article · Aug 2014 · Oncogene
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    ABSTRACT: Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor (MITF) in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down-regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma.
    Full-text · Article · Jun 2014 · Neoplasia (New York, N.Y.)
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    ABSTRACT: Deregulation of signaling pathways that control differentiation, expansion and migration of neural crest-derived melanoblasts during normal development contributes also to melanoma progression and metastasis. Although several epithelial-to-mesenchymal (EMT) transcription factors, such as zinc finger E-box binding protein 1 (ZEB1) and ZEB2, have been implicated in neural crest cell biology, little is known about their role in melanocyte homeostasis and melanoma. Here we show that mice lacking Zeb2 in the melanocyte lineage exhibit a melanoblast migration defect and, unexpectedly, a severe melanocyte differentiation defect. Loss of Zeb2 in the melanocyte lineage results in a downregulation of the Microphthalmia-associated transcription factor (Mitf) and melanocyte differentiation markers concomitant with an upregulation of Zeb1. We identify a transcriptional signaling network in which the EMT transcription factor ZEB2 regulates MITF levels to control melanocyte differentiation. Moreover, our data are also relevant for human melanomagenesis as loss of ZEB2 expression is associated with reduced patient survival.Cell Death and Differentiation advance online publication, 25 April 2014; doi:10.1038/cdd.2014.44.
    No preview · Article · Apr 2014 · Cell death and differentiation

Publication Stats

6k Citations
1,068.84 Total Impact Points

Institutions

  • 2010-2015
    • University of Strasbourg
      Strasburg, Alsace, France
  • 1994-2015
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1987-2015
    • Institut de Génétique et de Biologie Moléculaire et Cellulaire
      • Department of Functional Genomics and Cancer
      Strasburg, Alsace, France
  • 2013
    • La Ligue contre le cancer
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Cardiff University
      • School of Biosciences
      Cardiff, WLS, United Kingdom
  • 1997-2007
    • French Institute of Health and Medical Research
      • Institute of Genetics and Molecular and Cellular Biology
      Lutetia Parisorum, Île-de-France, France
  • 2002
    • Università degli Studi di Modena e Reggio Emilia
      Modène, Emilia-Romagna, Italy
    • Vanderbilt University
      • Department of Molecular Physiology and Biophysics
      Нашвилл, Michigan, United States
  • 1995-1996
    • Collège de France
      Lutetia Parisorum, Île-de-France, France
  • 1993
    • University of Pennsylvania
      • Department of Medicine
      Filadelfia, Pennsylvania, United States