ÉQUIPE
Mécanismes de régulation des gènes par des facteurs de transcription
Responsable d'équipe : Y. Graba ; A. Saurin
Nous étudions la fonction des facteurs de transcription Hox, visant à identifier les processus physiologiques sous leur contrôle ainsi que les mécanismes qui sous-tendent la spécificité et la diversité de la régulation des gènes.
RÉSUMÉ GRAND PUBLIC
La régulation des gènes est au cœur des processus physiologiques et pathologiques et, bien que ce ne soit pas exclusif, elle repose sur l’activité des facteurs de transcription qui forment de grands complexes multiprotéiques régulateurs. On sait peu de choses sur la façon dont ces complexes régulateurs s’assemblent et sur ce qui sous-tend leur spécificité et leur diversité fonctionnelles. Nos projets visent à explorer les processus contrôlés par les facteurs de transcription Hox, une famille de protéines conservées qui jouent un rôle clé dans le développement, l’évolution et les maladies, ainsi qu’à déchiffrer leur fonctionnement.
RÉSUMÉ SPÉCIALISTES
Pour appréhender la manière dont les processus cellulaires sont contrôlés par les facteurs de transcription, nous nous concentrons sur la fonction des facteurs de transcription Hox contenant des homedomaines. Les protéines Hox sont codées par des gènes généralement regroupés sur le chromosome, avec jusqu’à 39 gènes chez les vertébrés qui peuvent être regroupés en 13 groupes paralogiques selon leur origine phylogénétique et leur position dans le groupe Hox. Des études ont établi l’importance des protéines Hox dans le développement, chaque protéine de groupe paralogique contrôlant des programmes de développement distincts qui se traduisent par une morphogenèse axiale diversifiée (1). Les protéines Hox sont également au cœur de la biologie des cellules souches et des maladies.

Hox gene complexes and expression in flies and vertebrates
Malgré notre connaissance approfondie de la fonction de développement des protéines Hox, l’étendue des processus cellulaires contrôlés par Hox et la façon dont les protéines Hox réalisent la régulation transcriptionnelle nécessitent beaucoup plus de connaissances. Notre activité de recherche s’inscrit dans deux directions principales :
La première direction de recherche vise à caractériser les nouveaux processus cellulaires contrôlés par les protéines Hox. Bien que leur rôle dans la promotion de la morphogenèse différentielle axiale, où des paralogues Hox distincts fournissent des fonctions distinctes, nous avons récemment découvert des processus cellulaires où les protéines Hox semblent agir d’une manière non spécifique aux paralogues (2,3). Ceci est illustré par la régulation des processus cellulaires basaux tels que l’autophagie.

Generic and specific Hox functions
Le deuxième axe de recherche vise à comprendre comment les protéines Hox fonctionnent au niveau mécaniste, y compris dans des situations où elles agissent de manière paralogique et non spécifique. La plupart de nos connaissances sur le mode d’action des protéines Hox proviennent jusqu’à présent de l’étude de leur interaction avec les cofacteurs de la classe PBC, en particulier dans leur fonction de positionnement axial spécifique paralogique. Nous cherchons à identifier de nouveaux cofacteurs Hox, en particulier ceux qui éclairent les mécanismes de transcription qui sous-tendent leurs fonctions spécifiques non par analogues.

M1BP, an RNA PolII pausing factor and novel Hox cofactor
L’approche adoptée est de nature multidisciplinaire, utilisant la génomique, la transcriptomique et la protéomique pour définir le paysage réglementaire ; la biochimie, la biologie structurale et la modélisation moléculaire pour saisir les détails atomiques des mécanismes, et la génétique moléculaire pour sonder le fonctionnement in vivo. L’intégration de ces nouvelles connaissances devrait permettre de dégager de nouveaux aspects de la biologie et des mécanismes des fonctions de la protéine Hox. Nous pensons que cela est essentiel pour comprendre les bases de la régulation des gènes pendant le développement et l’évolution, et à plus long terme pour manipuler l’activité des facteurs de transcription et la régulation des gènes dans la biologie des cellules souches et des maladies.
(1) – Rezsohazy R., Saurin A. J., Maurel-Zaffran C. and Graba Y. (2015). Cellular and molecular insights into Hox protein action. Development, Apr 1;142(7):1212-1227. Review(2) – Banreti A, Hudry B, Sass M, Saurin AJ, Graba Y( 2014). Hox proteins mediate developmental and environmental control of autophagy. Developmental Cell. Jan 13;28(1):56-69.
(3) – Saurin AJ, Delfini MC, Maurel-Zaffran C, Graba Y (2018) The Generic Facet of Hox Protein Function. Trends in Genetics. Sep 18. pii: S0168-9525(18)30138-0.
(4) – Zouaz A, Auradkar A, Delfini MC, Macchi M, Barthez M, Ela Akoa S, Bastianelli L, Xie G, Deng WM, Levine SS, Graba Y, Saurin AJ (2017). The Hox proteins Ubx and AbdA collaborate with the transcription pausing factor M1BP to regulategene transcription. EMBO J. Oct 2;36(19):2887-2906.
Selected publications
PUBLICATION
August 7th, 2020
Stem cell regionalization during olfactory bulb neurogenesis depends on regulatory interactions between Vax1 and Pax6
PUBLICATION
June 15th, 2020
Human ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy regulation
PUBLICATION
January 21st, 2020
Loss of bhlha9 impairs thermotaxis and formalin-evoked pain in a sexually dimorphic manner
PUBLICATION
October 15th, 2019
Cooperation of axial and sex specific information controls Drosophila female genitalia growth by regulating the Decapentaplegic pathway
PUBLICATION
May 21st, 2019
PLZF limits enhancer activity during hematopoietic progenitor aging
PUBLICATION
December 22nd, 2018
The Generic Facet of Hox Protein Function
PUBLICATION
September 22nd, 2018
Post-translational modifications of HOX proteins, an underestimated issue
PUBLICATION
September 22nd, 2018
Fattening the perspective of Hox protein specificity through SLiMming
PUBLICATION
August 8th, 2018
Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer
PUBLICATION
October 2nd, 2017
The Hox proteins Ubx and AbdA collaborate with the transcription pausing factor M1BP to regulate gene transcription.
PUBLICATION
April 1st, 2017
Hox functional diversity: Novel insights from flexible motif folding and plastic protein interaction
PUBLICATION
December 19th, 2016
Hox Service Warranty Extends to Adult Bone Repair.
PUBLICATION
March 8th, 2016
Modular activation of Rho1 by GPCR signalling imparts polarized myosin II activation during morphogenesis
PUBLICATION
January 21st, 2016
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
PUBLICATION
November 15th, 2015
A survey of conservation of sea spider and Drosophila Hox protein activities.
PUBLICATION
September 1st, 2015
Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy
PUBLICATION
April 1st, 2015
Cellular and molecular insights into Hox protein action.
PUBLICATION
February 3rd, 2015
A flexible extension of the Drosophila ultrabithorax homeodomain defines a novel Hox/PBC interaction mode.
PUBLICATION
January 15th, 2015
Autophagy : Moving Benchside Promises to Patient Bedsides.
PUBLICATION
May 1st, 2014
Drosophila Hox transcription factors access the RNA Polymerase II machinery through direct homeodomain binding to a conserved motif of Mediator subunit Med19
PUBLICATION
January 15th, 2014
Hox genes : a fertile interplay of concepts and methods.
PUBLICATION
January 13th, 2014
Hox proteins mediate developmental and environmental control of autophagy.
PUBLICATION
October 24th, 2013
Distinct genetic requirements for BX-C mediated specification of abdominal denticles.
PUBLICATION
June 1st, 2013
The emerging role of acetylation in the regulation of autophagy.
PUBLICATION
February 21st, 2013
Distinct molecular strategies for Hox-mediated limb suppression in Drosophila: from cooperativity to dispensability/antagonism in TALE partnership.
PUBLICATION
February 21st, 2013
Antagonism Versus Cooperativity with TALE Cofactors at the Base of the Functional Diversification of Hox Protein Function.
PUBLICATION
February 21st, 2012
Hox proteins display a common and ancestral ability to diversify their interaction mode with the PBC class cofactors.
PUBLICATION
February 21st, 2012
The MYST-containing protein Chameau is required for proper sensory organ specification during Drosophila thorax morphogenesis.
PUBLICATION
October 1st, 2011
Insights into Hox protein function from a large scale combinatorial analysis of protein domains.
PUBLICATION
September 20th, 2011
Characterisation of genome-wide PLZF/RARA target genes.
PUBLICATION
February 8th, 2011
Selection of distinct Hox-Extradenticle interaction modes fine-tunes Hox protein activity.
PUBLICATION
January 28th, 2011
Visualization of protein interactions in living Drosophila embryos by the bimolecular fluorescence complementation assay.
PUBLICATION
September 1st, 2010
Control of DNA replication: a new facet of Hox proteins?
PUBLICATION
July 1st, 2010
Reiterative use of signalling pathways controls multiple cellular events during Drosophila posterior spiracle organogenesis.
PUBLICATION
January 1st, 2010
Regulation of Hox activity: insights from protein motifs.
PUBLICATION
May 15th, 2009
The PRC1 Polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation
PUBLICATION
May 1st, 2009
Classification of sequence signatures: a guide to Hox protein function.
PUBLICATION
March 1st, 2008
Reptin and Pontin function antagonistically with PcG and TrxG complexes to mediate Hox gene control.
PUBLICATION
October 23rd, 2007
A unique Extradenticle recruitment mode in the Drosophila Hox protein Ultrabithorax.
PUBLICATION
January 1st, 2006
Chameau HAT and DRpd3 HDAC function as antagonistic cofactors of JNK/AP-1-dependent transcription during Drosophila metamorphosis.
PUBLICATION
September 1st, 2005
Getting a molecular grasp on Hox contextual activity.
PUBLICATION
July 1st, 2005
Hox-controlled reorganisation of intrasegmental patterning cues underlies Drosophila posterior spiracle organogenesis.
PUBLICATION
November 1st, 2003
Tgfbeta signaling acts on a Hox response element to confer specificity and diversity to Hox protein function.
PUBLICATION
May 1st, 2003
The hexapeptide and linker regions of the AbdA Hox protein regulate its activating and repressive functions.
PUBLICATION
March 1st, 2003
Hox genes and apoptosis, from architecture to sculpture.
PUBLICATION
September 1st, 2002
A green fluorescent protein reporter genetic screen that identifies modifiers of Hox gene function in the Drosophila embryo.
PUBLICATION
April 30th, 2002
The MYST domain acetyltransferase Chameau functions in epigenetic mechanisms of transcriptional repression.
PUBLICATION
April 15th, 2001
DWnt4 and wingless elicit similar cellular responses during imaginal development.
PUBLICATION
June 1st, 2000
Dynamic expression of d-CdGAPr, a novel Drosophila melanogaster gene encoding a GTPase activating protein.
PUBLICATION
April 11th, 2000
Distinct hox protein sequences determine specificity in different tissues.
PUBLICATION
August 14th, 2014
Plasticity versus specificity in RTK signalling modalities for distinct biological outcomes in motor neurons
PUBLICATION
October 31st, 2013
TAFA4, a Chemokine-like Protein, Modulates Injury-Induced Mechanical and Chemical Pain Hypersensitivity in Mice.
PUBLICATION
June 9th, 2013
Deregulation of the Protocadherin Gene FAT1 Alters Muscle Shapes: Implications for the Pathogenesis of Facioscapulohumeral Dystrophy.
PUBLICATION
August 3rd, 2011
Pool-specific regulation of motor neuron survival by neurotrophic support.
PUBLICATION
May 1st, 2011
Stable, conditional, and muscle-fiber-specific expression of electroporated transgenes in chick limb muscle cells
PUBLICATION
September 15th, 2009
The timing of emergence of muscle progenitors is controlled by an FGF/ERK/SNAIL1 pathway
PUBLICATION
September 22nd, 2008
Telomeric trans-silencing in Drosophila melanogaster: tissue specificity, development and functional interactions between non-homologous telomeres
PUBLICATION
April 27th, 2007
A molecular clock operates during chick autopod proximal-distal outgrowth
PUBLICATION
August 1st, 2006
Liprin-alpha has LAR-independent functions in R7 photoreceptor axon targeting.
PUBLICATION
August 9th, 2005
Control of the segmentation process by graded MAPK/ERK activation in the chick embryo
PUBLICATION
February 1st, 2004
Ectopic Myf5 or MyoD prevents the neuronal differentiation program in addition to inducing skeletal muscle differentiation, in the chick neural tube
PUBLICATION
November 27th, 2002
Reptin and pontin antagonistically regulate heart growth in zebrafish embryos.
PUBLICATION
December 1st, 2001
Direct imaging of human SWI/SNF-remodeled mono- and polynucleosomes by atomic force microscopy employing carbon nanotube tips
PUBLICATION
October 25th, 2001
Cell-autonomous and -nonautonomous functions of LAR in R7 photoreceptor axon targeting.
PUBLICATION
September 1st, 2001
Reconstitution of a functional core polycomb repressive complex.
PUBLICATION
August 9th, 2001
A Drosophila Polycomb group complex includes Zeste and dTAFII proteins
PUBLICATION
March 1st, 2001
Purification and characterization of mSin3A-containing Brg1 and hBrm chromatin remodeling complexes.
PUBLICATION
January 1st, 2001
Notch signalling acts in postmitotic avian myogenic cells to control MyoD activation
PUBLICATION
December 1st, 2000
Delta 1-activated notch inhibits muscle differentiation without affecting Myf5 and Pax3 expression in chick limb myogenesis
PUBLICATION
September 15th, 2000
HPC3 is a new human polycomb orthologue that interacts and associates with RING1 and Bmi1 and has transcriptional repression properties
PUBLICATION
September 1st, 2000
Paraxis is expressed in myoblasts during their migration and proliferation in the chick limb bud
PUBLICATION
July 2nd, 2000
dlarp, a new candidate Hox target in Drosophila whose orthologue in mouse is expressed at sites of epithelium/mesenchymal interactions
PUBLICATION
July 1st, 2000
The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals
PUBLICATION
March 1st, 2000
pannier acts upstream of wingless to direct dorsal eye disc development in Drosophila
PUBLICATION
August 1st, 1999
nessy, an evolutionary conserved gene controlled by Hox proteins during Drosophila embryogenesis
PUBLICATION
July 1st, 1999
Antagonist activity of DWnt-4 and wingless in the Drosophila embryonic ventral ectoderm and in heterologous Xenopus assays.
PUBLICATION
April 29th, 1999
SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex.
PUBLICATION
April 1st, 1999
Identification of the t(15;17) in AML FAB types other than M3: evaluation of the role of molecular screening for the PML/RARalpha rearrangement in newly diagnosed AML. The Medical Research Council (MRC) Adult Leukaemia Working Party
PUBLICATION
February 1st, 1999
SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation
PUBLICATION
August 24th, 1998
The human polycomb group complex associates with pericentromeric heterochromatin to form a novel nuclear domain
PUBLICATION
May 1st, 1998
Wnt and TGFbeta signals subdivide the AbdA Hox domain during Drosophila mesoderm patterning.
PUBLICATION
July 1st, 1997
RING1 is associated with the polycomb group protein complex and acts as a transcriptional repressor.
PUBLICATION
May 1st, 1997
Drosophila Hox complex downstream targets and the function of homeotic genes.
PUBLICATION
April 1st, 1997
Hox genes in evolution: protein surfaces and paralog groups.
PUBLICATION
October 10th, 1996
The Drosophila teashirt homeotic protein is a DNA-binding protein and modulo, a HOM-C regulated modifier of variegation, is a likely candidate for being a direct target gene.
PUBLICATION
June 1st, 1996
Does this have a familiar RING?
PUBLICATION
January 1st, 1996
Inhibition of mitogen-induced DNA synthesis by bafilomycin A1 in Swiss 3T3 fibroblasts
PUBLICATION
November 1st, 1995
wingless and DWnt4, 2 Drosophila Wnt genes, have related expression, regulation and function during the embryonic development.
PUBLICATION
March 10th, 1995
Genetic and molecular analysis of terminal deletions of chromosome 3R of Drosophila melanogaster.
PUBLICATION
January 1st, 1995
DWnt-4, a novel Drosophila Wnt gene acts downstream of homeotic complex genes in the visceral mesoderm.
PUBLICATION
December 1st, 1994
The modifier of variegation modulo gene acts downstream of dorsoventral and HOM-C genes and is required for morphogenesis in Drosophila.
PUBLICATION
October 1st, 1993
A quick method for immunoscreening recombinant bacterial colonies.
PUBLICATION
December 1st, 1992
Cell lineage-specific expression of modulo, a dose-dependent modifier of variegation in Drosophila.
PUBLICATION
September 1st, 1992