Interactions gène-nutrition dans le cadre des maladies cardiaques congénitales

L'idée que la vaste majorité des maladies humaines ne sont ni le résultat d'une exposition environnementale isolée ni celui de la mutation d'un gène unique est largement admise et étayée par de nombreuses publications. Le plus souvent, les effets des facteurs de risque génétiques et environnementaux se conjuguent. Parmi les anomalies congénitales résultant d'une interaction gènes–environnement, figurent les malformations cardiaques pour lesquelles à ce jour les mécanismes physiopathologiques et les interactions gènes-environnement associés demeurent inconnues.

Les causes non génétiques à l’origine des malformations cardiaques congénitales comprennent notamment les tératogènes environnementaux tels que l’exposition maternelle excessive à la vitamine A et à ses dérivés rétinoïdes (par exemple l'isotrétinoïne). Il est également établi qu’un diabète maternel présent avant ou pendant la grossesse est associé à un plus grand risque de développer une maladie cardiovasculaire congénitale (risque augmenté par 5). Les mécanismes moléculaires sous-jacents à ces pathologies, dont le pronostic vital des fœtus et nouveau-nés peut être engagé, ne sont pas totalement élucidés. Les travaux de recherche du Dr Sonia Stefanovic portent actuellement sur les conséquences de la dérégulation de la voie de signalisation de la vitamine A et l'impact du diabète maternel sur les maladies congénitales cardiaques.

Ces projets sont soutenus par H2020-MSCA-IF-2014 et ERA-CVD-2019 et intègrent des approches de biologie moléculaire innovantes (permettant l’étude du transcriptome et de l’épigénome) ainsi que des cohortes de patients, ceci afin d’étudier l'impact de ces facteurs environnementaux sur les maladies cardiaques congénitales et permettre l’élaboration d’outils de diagnostic chez les femmes en âges de procréer.



Publications du groupe

Stefanovic, S.  et al. 2020

Hox-dependent coordination of mouse cardiac progenitor cell patterning and differentiation

Perturbation of addition of second heart field (SHF) cardiac progenitor cells to the poles of the heart tube results in congenital heart defects (CHD). The transcriptional programs and upstream...
eLife - issue: - volume: 9 - pages: e55124.

van Eif, V.  et al. 2019

Transcriptome analysis of mouse and human sinoatrial node cells reveals a conserved genetic program

The rate of contraction of the heart relies on proper development and function of the sinoatrial node, which consists of a small heterogeneous cell population, including Tbx3(+) pacemaker cells. Here,...
Development - issue: - volume: 146 (8) - pages: dev173161.

van Eif, VW. W.  et al. 2019

Gradual differentiation and confinement of the cardiac conduction system as indicated by marker gene expression

The components of the cardiac conduction system, responsible for coordinated activation of the heart chambers, are well defined and their cells differ in gene expression profile and phenotype from...
Biochim Biophys Acta Mol Cell Res - issue: 3 - volume: 1867 - pages: 118509.

De Bono, C.  et al. 2018

T-box genes and retinoic acid signaling regulate the segregation of arterial and venous pole progenitor cells in the murine second heart field

The arterial and venous poles of the mammalian heart are hotspots of congenital heart defects (CHD) such as those observed in 22q11.2 deletion (or DiGeorge) and Holt–Oram syndromes. These regions of...
Hum Mol Genet - issue: 21 - volume: 27 - pages: 3747-3760.

Zaffran, S.  et al. 2018

Ectopic expression of Hoxb1 induces cardiac and craniofacial malformations

Members of the large family of Hox transcription factors are encoded by genes whose tightly regulated expression in development and in space within different embryonic tissues confer positional...
Genesis - issue: 5-6 - volume: 56 - pages: e23221.

Métais, A.  et al. 2018

Asb2α-Filamin A Axis Is Essential for Actin Cytoskeleton Remodeling During Heart Development.

RATIONALE: Heart development involves differentiation of cardiac progenitors and assembly of the contractile sarcomere apparatus of cardiomyocytes. However, little is known about the mechanisms that...
Circ Res - issue: 6 - volume: 122 - pages: e34-e48.

Roux, M.  et al. 2017

Hoxa1 and Hoxb1 are required for pharyngeal arch artery development

Hox transcription factors play critical roles during early vertebrate development. Previous studies have revealed an overlapping function of Hoxa1 and Hoxb1 during specification of the rhombomeres...
Mech Dev - issue: - volume: 143 - pages: 1-8.

Stefanovic, S.  et al. 2017

Mechanisms of retinoic acid signaling during cardiogenesis

Substantial experimental and epidemiological data have highlighted the interplay between nutritional and genetic factors in the development of congenital heart defects. Retinoic acid (RA), a...
Mech Dev - issue: - volume: 143 - pages: 9-19.

Stefanovic, S.  et al. 2015

GATA-dependent transcriptional and epigenetic control of cardiac lineage specification and differentiation

Heart progenitor cells differentiate into various cell types including pacemaker and working cardiomyocytes. Cell-type specific gene expression is achieved by combinatorial interactions between...
Cellular and molecular life sciences : CMLS - issue: 20 - volume: 72 - pages: 3871-81.

Abboud, N.  et al. 2015

A cohesin-OCT4 complex mediates Sox enhancers to prime an early embryonic lineage.

Short- and long-scales intra- and inter-chromosomal interactions are linked to gene transcription, but the molecular events underlying these structures and how they affect cell fate decision during...
Nat Commun - issue: - volume: 6 - pages: 6749.

Mohan, RA.  et al. 2014

A mutation in the Kozak sequence of GATA4 hampers translation in a family with atrial septal defects.

Atrial septal defect (ASD) is the most common congenital heart defect clinically characterized by an opening in the atrial septum. Mutations in GATA4, TBX5, and
Am J Med Genet A - issue: 11 - volume: 164A - pages: 2732-2738.

van Weerd, JH.  et al. 2014

A large permissive regulatory domain exclusively controls Tbx3 expression in the cardiac conduction system

RATIONALE: The evolutionary conserved Tbx3/Tbx5 gene cluster encodes T-box transcription factors that play crucial roles in the development and homeostasis of the cardiac conduction system in human...
Circ Res - issue: 4 - volume: 115 - pages: 432-41.

Stefanovic, S.  et al. 2014

GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development

The embryonic vertebrate heart tube develops an atrioventricular canal that divides the atrial and ventricular chambers, forms atrioventricular conduction tissue and organizes valve development. Here...
Nat Commun - issue: - volume: 5 - pages: 3680.

Neri, T.  et al. 2010

Cardiac regeneration: still a 21st century challenge in search for cardiac progenitors from stem cells and embryos.

Regeneration of the heart after a stroke would be the best biologic response to restore its function. However, although this phenomenon occurs in primitive organisms, the regenerative potential is...
J Cardiovasc Pharmacol - issue: 1 - volume: 56 - pages: 16-21.

Blin, G.  et al. 2010

A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates

Cell therapy holds promise for tissue regeneration, including in individuals with advanced heart failure. However, treatment of heart disease with bone marrow cells and skeletal muscle progenitors has...
The Journal of clinical investigation - issue: 4 - volume: 120 - pages: 1125-39.

Stefanovic, S.  et al. 2010

[The dual role of OCT4].

OCT4 encoded by pou5f1 is one of the most ancient and early transcription factors identified in the embryo. It has been longwise recognized as a gatekeeper for pluripotency of embryonic stem (ES)...
Med Sci (Paris) - issue: 4 - volume: 26 - pages: 411-416.

Stefanovic, S.  et al. 2009

Interplay of Oct4 with Sox2 and Sox17: a molecular switch from stem cell pluripotency to specifying a cardiac fate

Oct4 exerts a dose-dependent dual action, as both a gatekeeper for stem cell pluripotency and in driving cells toward specific lineages. Here, we identify the molecular mechanism underlying this dual...
The Journal of cell biology - issue: 5 - volume: 186 - pages: 665-73.

Leschik, J.  et al. 2008

Cardiac commitment of primate embryonic stem cells

Primate nonhuman and human embryonic stem (ES) cells provide a powerful model of early cardiogenesis. Furthermore, engineering of cardiac progenitors or cardiomyocytes from ES cells offers a tool for...
Nature protocols - issue: 9 - volume: 3 - pages: 1381-7.

Stefanovic, S.  et al. 2007

Oct-3/4: not just a gatekeeper of pluripotency for embryonic stem cell, a cell fate instructor through a gene dosage effect.

Oct-3/4 encoded by Pou5f1 has been longwise recognised as a gatekeeper for embryonic stem (ES) cell pluripotency. Recently, it was suggested that Oct-3/4 one of the earliest transcription factor of...
Cell Cycle - issue: 1 - volume: 6 - pages: 8-10.