Expression of genetic information
In humans, many factors involved in the regulation of gene expression and the control of genome integrity are macromolecular assemblies, whose composition and activity vary during development and can be modulated by drugs in normal and pathological conditions. Our work is focused on multi-protein complexes involved in transcription and its regulation, and particularly, the TFIIH factor involved in transcription initiation and regulation as well as DNA repair by nucleotide excision, nuclear hormone receptors (NHR) and their co-regulators. The transcriptional activity of nuclear receptors is not only regulated by ligand binding, but also by post-translational modifications that often participate in the recruitment of co-regulators, chromatin remodeling complexes and components of the basal transcriptional machinery.
Our goal is to understand the mechanisms that control gene expression through integrative structural biology approaches in order to obtain information from the atomic to the cellular scale, using biophysical characterization techniques, structural studies in solution, electron cryo-microscopy and crystallography. Since many macromolecular complexes associate transiently, the temporal component as well as reconstitution of the proper sequence of cellular events using light microscopy tools can be crucial steps. Our projects aim to shed new light on transcriptional control mechanisms at the molecular scale, a better understanding of which will open new perspectives with probable therapeutic benefits.
We also study the HIV integrase that plays a key role in the viral cycle and recruits cellular proteins from the host, including the transcription factor INI1, an essential component of the chromatin remodeling complex SWI/SNF, and the derived growth factor (LEDGF) or p300, a co-activator of many NHRs.
We investigate the structure and function of transcription complexes, in particular to unravel the molecular basis of regulation by nuclear hormone receptors as well as their interactions with the basal transcriptional machinery. The structural characterization of these macromolecular systems poses a significant challenge, not only because of their complexity and the necessity to obtain well-defined and homogeneous samples, but also because of their dynamic nature and the need to integrate temporal data concerning their recruitment on the promoters of target genes. Our main research axes concern (i) the study at the atomic scale of the allosteric control of NHR activity through their DNA binding elements, (ii) the characterization and structural study of NHR/co-regulator complexes, (iii) the study of the molecular architecture of the transcription/repair factor TFIIH and communication mechanisms with other transcription and/or repair complexes, (iv) the analysis of spatial and temporal events occurring on an activated gene in a cellular environment, (v) the study of DNA transfer mechanisms by retroviral integrases (HIV).
We use integrative structural biology approaches combining X-ray crystallography, small-angle scattering and cryo-microscopy techniquees for multiscale structural studies, nuclear magnetic resonance, fluorescence microscopy and other biophysics approaches for functional and dynamic analyses. As preparation and characterization of molecular and cellular samples are bottlenecks in many projects, we are investing significant efforts to develop technologies required to solve these problems. These studies are performed in the framework of the European infrastructure for integrated structural biology INSTRUCT (www.instruct-fp7.eu) and its national counterpart, the French infrastructure for integrated structural biology (FRISBI).
Strong internal collaborations within the department of structural biology with the groups of electronic microscopy, NMR and bioinformatics as well as with groups from the department of functional genomics (Irwin Davidson, Fréderic Coin and Jean Marc Egly, Daniel Metzger and Pierre Chambon, …).
External national and international collaborations:
- SAXS : Dmitry Svergun, EMBL Hamburg, Germany
- Masspectrometry : Renato Zenobi, ETH, Zurich, Switzerland ; Alain Van Dorsselaer, IPHC CNRS, Strasbourg, France ; Noelle Potier, Institut de Chimie, Strasbourg, France
- NMR : Lucia Banci, CRM, Florence, Italie
- Hormone nuclear receptors: Vincent Laudet, ENS, Lyon, France ; Gunther Schütz, DKFZ, Heidelberg, Germany ; Antonio Mouriño, Universidad de Santiago de Compostela Facultad de Química Santiago de Compostela, Spain
- Viral integrases : Stéphane Emiliani, Institut Cochin, Paris, France ; Yves Mely, Faculté de Pharmacie, Strasbourg, France
- Dino MORAS - Officier de l'Ordre national du mérite - Etat français - 2014
- Natacha ROCHEL-GUIBERTEAU - Scientific prize - Fondation pour la Recherche Médicale (FRM) - 2012
- Dino MORAS - Chevalier of the Legion of Honour - Etat français - 2002
- Dino MORAS - Member of the French Academy of science - Académie des sciences - 1999
- Dino MORAS - Member of the European Molecular Biology Organization (EMBO) - European Molecular Biology Organization (EMBO) - 1987
- Dino MORAS - Silver Medal - CNRS - 1982
- Dino MORAS - Bronze Medal - CNRS - 1972
- Jan. 22, 2015 - Discovery of a dark side of vitamin D deficiency: the repressive activity of its receptor
- Feb. 23, 2012 - Official launching of the ESFRI integrative structural biology infrastructure : INSTRUCT
- Jan. 17, 2012 - First complete 3D mapping of vitamin D receptor
- April 10, 2011 - Nuclear receptors 3D structure in the spot light
J Biol Chem May 23, 2016 ; 291:14430-14446 .
Biochemistry March 29, 2016 ; 55:1741-8 .
Chemical Science 2016 2016 ; 7:1033-1037 .
Vitam Horm 2016 ; 100:83-116 .
Biophys Chem Mar 2016 ; 210:2-8 .
Bioengineered Nov. 2, 2015 ; 6:316-22 .
PLoS Genet June 1, 2015 ; 11:e1005213 .
Trends Biochem Sci Jun 2015 ; 40:287-90 .
Biochimie Oct 2015 ; 117:63-71 .
Methods Mol Biol 2015 ; 1258:181-205 .