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Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2018
Renseignements relatifs à l’Unité de Recherche :
Label et intitulé : Institut Cochin
Nom et prénom du Directeur : COURAUD Pierre-Olivier
Téléphone :
Télécopie :
courriel :
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : « Expression Génique, Développement et Maladies »
Nom et prénom du responsable : PONTOGLIO Marco
Qualité du responsable : Directeur de recherche
Téléphone :
01 53 73 27 40
Télécopie :
courriel : [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) :PONTOGLIO Marco
Qualité : Directeur de recherche
Téléphone :
01 53 73 27 40
Télécopie :
courriel : [email protected]
Titre du sujet proposé :
(en français) Héritage épigénétique mitotique
(en anglais) Mitotic Epigenetic inheritance
Département (cocher le département correspondant au sujet de thèse qui n’est pas obligatoirement le
vôtre) :
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Biologie Cellulaire et moléculaire, Physiologie et Physiopathologie
Immunologie
Développement Génétique Neurobiologie et Vieillissement
Infectiologie, Microbiologie
Summary (5 lignes maximum) :
Mutations in the transcription factor HNF1B (HNF1beta), are frequently found in patients that suffer from
severe renal developmental defects. HNF1beta has the ability to bind mitotic chromosomes and behave
as a gene bookmarking factor. With a multidisciplinary approach, based on NGS gene expression
analysis, and ChIP-seq and molecular biology approaches, our project aims at understanding how the
bookmarking activity exerted by HNF1beta may lead to its critical control of gene expression.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2015-2016
Nom, prénom du directeur de l'unité de recherche :Pierre-Olivier Couraud
Numéro de l'unité de recherche (et établissement de rattachement) :Inserm U1016/CNRS 8104/UP5
Nom, prénom du responsable de l'équipe d'accueil (EAD) :Marco Pontoglio
Nom, prénom du directeur de thèse : PONTOGLIO Marco
Titre du sujet de thèse proposé :HNF1beta and the epigenetic control of gene expression
Citer 5 mots clés : Epigenetics; Bookmarking; Gene expression; Chromatin; Mitosis
Candidat pressenti :
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OUI
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NON
Contenu scientifique du programme de la thèse (en anglais)
At the beginning of mitosis, when the nuclear envelope is dissolved, many nuclear components,
including most transcription factors, dissociate from chromatin and freely diffuse in the cytoplasm. At the
same time, chromatin compaction leads to the typical packed and transcriptionally inactive mitotic
chromosomes. Remarkably, some transcription factors have the ability to remain associated with mitotic
chromatin. This suggested the idea that mitotically retained bookmarking factors could deliver an
epigenetic memory signal throughout mitosis to ensure the faithful transmission of genetic programs after
mitosis. The rapid reactivation of the proper parental gene expression pattern in daughter cells is
considered a key issue in regard to the epigenetic inheritance of cellular identity. Our recent studies have
demonstrated that Hepatocyte Nuclear Factor 1 alpha and beta (HNF1alpha and HNF1beta) are
bookmarking factors that can bind mitotic chromatin. These closely related proteins are dimeric
transcription factors that contain a POU homeobox domain and can form homo- or heterodimers that bind
to the same DNA sequences.
Human mutations in HNF1A and HNF1B are frequently associated to developmental and
postnatal dysfunctions of pancreas and kidney. We have shown that the inactivation of HNF1beta in
mouse may lead to polycystic kidney disease due to the loss of expression of target genes that are mutated
in renal polycystic patients. In this context, we disclosed a novel aspect in the control of gene expression:
we showed that some of the HNF1beta target genes (named Class 1) become transcriptionally silenced as
soon as HNF1beta is inactivated. On the other hand, some other target genes (named Class 2) remain
transcriptionally active and become silenced only when mutant cells undergo cell cycle. In addition, we
showed that in mutant post-mitotic cells the chromatin of HNF1beta target genes acquires several
heterochromatin marks. These results suggest that HNF1beta activates gene expression via two distinct
mechanisms: (1) by ensuring the maintenance of recruitment and activation of the transcriptional
machinery on the promoters of target (Class 1) genes and/or by (2) inducing the reopening of chromatin
of target (Class 2) genes after a transcriptional silencing mitotic chromatin condensation.
Our working hypothesis is that the binding of HNF1alpha and/or HNF1beta to specific mitotic
chromatin sites might provide an epigenetic landscape that endows the nearby bookmarked target genes
the ability to be efficiently transcriptionally reactivated after mitosis. Relatively little is known about the
mechanisms through which bookmarking transcription factors are able to persist on mitotic chromatin. In
addition, the epigenetic consequences induced by bookmarking factors on mitotic chromatin are not fully
understood.
The present thesis project will (1) Identify the mitotic and interphase chromatin sites bound by
HNF1alpha and HNF1beta with a high-throughput ChIP-seq approach. (2) Characterize the epigenetic
landscape of mitotic and interphase HNF1s chromatin binding site with a Mass/Spectrometry (MS)
approach. (3) Identify proteins that interact with HNF1alpha and beta to confer the ability to bind mitotic
chromatin or activate postmitotic expression of target genes with a MS proteomic analysis. The
comprehension of the molecular mechanisms and the function of two bookmarking transcription factors
that are frequently mutated in patients suffering from important diseases should help shedding a new light
and novel perspectives in the potential development of novel targeted therapies.
Indiquez les cinq meilleures publications récentes de l’équipe :
Fischer et al. Nature Genetics 2006 // Verdeguer F et al. Nature Medicine 2010// Massa F et al.
Development 2013 // Lerner et al. Nucleic Acids Research 2016// Garcia-Gonzalez MA et al.
Scientific Reports