Gene-diet interactions and congenital heart diseases

Congenital heart disease, defined as a gross structural abnormality of the heart, is the most common type of human birth defect, occurring in ∼9 per 1000 live births and at a significantly greater incidence in miscarriage and still births. The complexity in understanding the etiology of congenital heart diseases is heightened by disease variability influenced by genetic, epigenetic and/or environmental modifiers. Environmental factors are known to contribute to CHDs, but the pathophysiology and associated gene-environment interactions are not well-known. Well-recognized nongenetic causes of CHDs include environmental teratogens, such as excess maternal exposures to Vitamin A and its retinoid derivatives (e.g. isotretinoin). Pregestational maternal diabetes is a well-established adverse environment for embryonic development, due to fetal exposure to elevated blood glucose levels. It is associated with a 5X increase in CHD incidence. The molecular mechanisms underlying these lethal effects are not well understood. Dr Sonia Stefanovic is currently studying the consequence of deregulated Vitamin A signaling on mouse embryos genetically predisposed to heart defects and the impact of maternal diabetes on CHDs, projects being supported by H2020-MSCA-IF-2014 and ERA-CVD-2019.



Team Publications

Stefanovic, S.  et al. 2020

Hoxb1 functions in a subset of cardiac progenitor cells to establish and maintain the proper development of the second heart field


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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...
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van Eif, VW. W.  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,...
- issue: 8 - volume: 146 - pages: .

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...
- 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...
- issue: 6-7 - 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...
- 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...
Mechanisms of development - 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.

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...
Nature communications - issue: - volume: 5 - pages: 3680.

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...
- issue: 4 - volume: 115 - pages: 432-41.

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.