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Regulation of heart development and function through combinatorial interactions of transcription factors Georges Nemer and Mona Nemer
Understanding the molecular mechanisms controlling cardiac-specific gene transcription requires the dissection of the cis-elements that govern the complex spatiotemporal expression of these genes. The four-chambered vertebrate heart is formed during the late phases of fetal development following a series of complex morphogenetic events that require the functional presence of different proteins. The gradient-like expression of some genes, as well as the chamber-specific expression of others, is tightly regulated by combinatorial interactions of several transcription factors and their cofactors. Chamber- and stagespecific cardiac myocyte cultures have been invaluable for identifying transcription factor binding sites involved in basal, chamber-specific, and inducible expression of many cardiac promoters; these studies, which were largely confirmed in vivo in transgenic mouse models, led to the isolation of key regulators of heart development. In addition, the use of pluripotent embryonic stem cells helped elucidate the early molecular events controlling cardiomyocyte differentiation. Together, these studies point to a major role for GATA transcription factors and their interacting partners in transcriptional control of heart development. In addition, members of the T-box family of transcription factors and homeodomain containing proteins, together with chamber-restricted transcriptional repressors and co-repressors play critical roles in heart septation and chamber specification. These fine-tuned cooperative interactions between different classes of proteins are at the basis of normal cardiac function, and alteration in their expression level or function leads to cardiac pathologies.
From the Department of Pharmacology, University of Montréal; and Laboratory of Cardiac Development and Differentiation, Clinical Research Institute of Montreal, Montréal, Québec, Canada. Correspondence: Mona Nemer, PhD, Laboratory of Cardiac Development and Differentiation, Clinical Research Institute of Montreal, 110 des Pins ouest, Montréal QC, Canada H2W 1R7. E-mail:
[email protected], Fax: +1 514 9875575.
Keywords: embryonic development; GATA transcription factors; gene expression regulation; heart; natriuretic peptides.
Ann Med 2001; 33: 604–610.
Introduction Cardiac pathologies remain the leading cause of embryonic and postnatal death in most industrialized countries. Defining the molecular pathways underlying normal heart development is a prerequisite step for understanding the molecular basis of congenital heart malformation and postnatal cardiac disease, and for developing appropriate therapeutic interventions. Analysis of the mechanisms of cardiac transcription by using the promoters of the two natriuretic peptide genes, atrial natriuretic factor (ANF) and B-type natriuretic peptide (BNP) have led to the identification of many key regulators of the cardiac genetic programme (1, 2). The natriuretic peptide genes represent early markers of differentiated cardiac myocytes, and their products, the circulating hormones ANF and BNP, act on many target organs to regulate volume homeostasis through their natriuretic, vasodilatory, and hypotensive effects. Their expression is tightly regulated spatially, developmentally, and hormonally, making them ideal tools for analysis of gene regulation in the heart (2). The dissection of the rat ANF promoter in cultured cardiac cells led to the identification of three regulatory modules within the first 700 bp of upstream sequences. These modules, which contain many binding sites for different classes of transcription factors, are conserved across species and are differentially active in atria and ventricles during development (1, 3, 4). Transgenes driven by either the human or the rat ANF –500 bp promoter recapitulate the spatio-temporal expression of the endogenous ANF gene in vivo (5, 6).
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Advances in molecular biology made by using the dissected regulatory elements found in the ANF promoter as well as other cardiac genes, such as those encoding the contractile proteins, allowed the isolation of novel transcription factors, which are required for normal cardiac development. In particular, the identification and functional analysis of the zinc finger transcription factor GATA-4 paved the way for the characterization of other transcription factors involved in cardiogenesis (7–9). The involvement of factors such as the homeobox Nkx2.5 protein, the basic helix-loop-helix (bHLH) Hand proteins, and the MADS transcription factors myocyte enhancer factor2 (MEF2) and serum response factor (SRF) in early heart development has in turn revealed that complex combinatorial interactions control basal and inducible expression of cardiac genes and therefore cardiac function (reviewed in (10)). In this review, we will focus on the pivotal roles of GATA-4 and NKx2.5 and their cooperative interactions with other cardiacenriched or ubiquitous factors to ensure proper spatio-temporal expression of cardiac genes during normal embryonic and postnatal cardiac development. The ANF promoter will be used to illustrate the combinatorial actions of these regulators on target promoters.
Cardiomyocyte differentiation In vertebrates, heart development begins during later stages of gastrulation. The cardiac myocytes and the endocardial endothelial cells compose the first two layers of the primitive heart tube, which is formed by the fusion of two crescent-shaped cell fields on both sides of the anteroposterior axis of the embryo. The cardiac-enriched transcription factors Nkx2.5 and GATA-4 are the earliest markers of the precardiac cells (9, 11) that originate from the lateral plate mesoderm. Prior to the formation of the heart tube,
Abbreviations and acronyms ANF BMP BNP CARP MAPK MEF2 MyHC3 NF-AT3 RXRα SRF TBE TGFβ VDR VDRE
atrial natriuretic factor bone morphogenetic protein B-type natriuretic peptide cardiac-restricted ankyrin repeat protein mitogen-activated protein kinase myocyte enhancer factor-2 quail slow myosin chain type 3 nuclear factor of activated T cells retinoid acid receptor serum response factor T-box element transforming growth factor beta vitamin D receptor vitamin D response element
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Key messages • Transcription factor GATA-4 is essential for various stages of heart development. • Combinatorial interactions between GATA-4 and different co-factors mediate its pleiotropic effects. • Combinatorial action of the homeodomain protein Nkx2.5 and the T-box transcription factor Tbx5 specifies atrial cell fate. • Nkx2.5/Tbx5 interaction explains why mutations in either gene lead to similar cardiac malformations.
precardiac cells already express several cardiacspecific genes, including those encoding contractile proteins and ANF, indicating that cardiomyocyte differentiation precedes the subsequent morphogenetic events that will lead to the formation of the heart. The use of the P19 stem cells helped establish a more detailed temporal hierarchy of gene expression during cardiomyocyte differentiation. Studies of gain-offunction for GATA-4 in P19 cells showed that GATA4 can only potentiate but does not initiate cardiac differentiation (12). Ectopic expression of Nkx2.5, GATA-4, GATA-5, and GATA-6 in Xenopus embryos also shows that alone these factors are not sufficient to induce cardiogenesis but instead they need to cooperate with others that are present in precardiac cells (13, 14). Given the fact that the ANF promoter was activated by both Nkx2.5 and GATA transcription factors through their respective DNAbinding sites, it was used to test the hypothesis that GATA factors and Nkx2.5 may be collaborators in cardiogenesis. In vitro and in vivo coprecipitation assays as well as pull-down experiments showed that both proteins can physically interact through the Cterminal zinc finger and adjacent basic region of GATA-4 and the C-terminally extended homeodomain of Nkx2.5 (15). Moreover, in vitro transactivation studies showed that GATA-4 and Nkx2.5 can synergistically activate the ANF promoter and that this cooperativity requires that both proteins bind the DNA. Two activation domains at the N and Cterminal region of GATA-4 as well as a repressor domain at the C-terminal region of Nkx2.5 are involved in this synergy. It is proposed that GATA-4 through its interaction with Nkx2.5 unmasks a Cterminal autorepressor domain of Nkx2.5 (4, 16). Additional studies showed that, in a context where GATA binding sites are lacking, Nkx2.5 can recruit GATA-4 and synergistically cooperate to activate target genes (17, 18). Thus, in addition to ANF, the
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GATA-4/Nkx2.5 interaction was further documented for two other cardiac promoters, the cardiac α-actin (19), and the cardiac-restricted ankyrin repeat protein CARP (20). The implication of the GATA-4/Nkx2.5 interaction in cardiomyocyte differentiation was clearly demonstrated in the P19CL6 cell line where over-expression of both GATA-4 and Nkx2.5 proved sufficient to induce the cardiac differentiation programme. Moreover, the GATA-4/Nkx2.5 interaction is targeted by the bone morphogenetic protein (BMP) signalling pathway through the mitogen-activated protein kinase (MAPK) Tak-1 (21), a mechanism conserved throughout evolution; in chicken, BMP-2 secreted from the endoderm induces GATA-4 and Nkx2.5 in the adjacent cardiac mesoderm (22), whereas in Drosophila, decapentaplegic dpp (a member of the transforming growth factor (TGF)-β family) secreted from the ectoderm is essential for inducing pannier, the GATA4 homologue, which through its interaction with tinman activates the differentiation of precardiac mesoderm into cardiomyocytes (23). One of the features of the GATA/Nkx2.5 interaction is its high specificity: NKx2.5 interacts with GATA-4 and GATA5 but not with GATA-6, suggesting that differential combinatorial interactions may account for functional specificity of different family members. Finally, the existence of NKE binding sites on the murine GATA-6 promoter essential for its activity in vivo (24) as well as the direct transcriptional regulation of zebrafish Nkx2.5 by GATA-5 in vivo (25, 26) suggest that the GATA and Nkx proteins interact at several levels. In addition to their importance in cardiomyocyte differentiation, combinatorial interactions between different cardiac-specific transcription factors are essential for the maintenance of cardiac gene expression and the cardiac phenotype in postnatal development. For example, both GATA-4 and GATA-6 proteins are essential for maintaining ANF expression in postnatal cardiomyocytes, a result of their cooperative interaction (27). The physical and functional interaction between GATA-4 and GATA-6 may explain why two or more members of the same family of transcription factors are coexpressed and act in a non-redundant manner. Another example of cooperativity between cardiacenriched transcription factors is the GATA/MEF2 interaction. In vitro analysis by pull down assays and co-immunoprecipitation show that members of the MEF2 family of MADS transcription factors interact directly with GATA-4 to activate downstream targets such as the ANF promoter. In fact, GATA-4 recruits MEF2 proteins to GATA binding sites, and MEF2 acts as a GATA coactivator (28). The GATA/MEF2 interaction explains the absence of ANF and other cardiac transcripts in the MEF2C knock-out mouse embryos, as their promoters do not contain high-affinity binding
sites for MEF2 but all are direct GATA targets (29). Interestingly, MEF2 proteins can be recruited by either GATA-4 or GATA-6 but not by GATA-5, providing one more example of combinatorial interaction specificity. Finally, GATA and MEF2 factors had been shown to interact physically with ubiquitously expressed cofactors possessing histone acetyltransferase activity such as p300 (30–33). The synergistic activation of downstream targets by the p300/GATA interaction and p300/MEF2 interaction, and the possible involvement of p300 in the GATA/MEF2 interaction further highlight the different checkpoints that govern cardiacspecific gene expression.
Chamber specification and morphogenesis Development of the mature heart involves further myocyte differentiation into two subtypes, atrial and ventricular, which will form the different heart chambers. This occurs early as the heart tube is already segmented into atrial (posterior) and ventricular (anterior) domains that are characterized by differential expression of several atrial and ventricular markers. However, only a handful of transcription factors have a strict chamber-specific pattern. Analysis of two atrial promoters, the quail slow myosin chain type 3 (MyHC3) and ANF, have provided insight into the mechanisms underlying chamber-specific gene expression and development (34–38), which again involves combinatorial interactions between various cell-restricted and ubiquitous regulators. MyHC3 becomes restricted to the atria just after formation of the heart tube. Analysis of the –840 bp sequences of the MyHC3 promoter in transgenic mice show that these sequences are sufficient to recapitulate the endogenous expression of the gene, ie its atrialspecific expression (34). In vitro, dissection of these sequences by using fetal and neonatal cardiomyocytes cultures shows that a GATA binding site is essential for atrial expression of the promoter, while a vitamin D response element (VDRE) is required for inhibition of the expression in the ventricles (35). The vitamin D receptor (VDR), and the retinoic acid receptor (RXα) form a heterodimer that binds the VDRE on the MyHC3 promoter and repress its activity in ventricles. However, none of the members of the retinoic acid nuclear receptor family, including the vitamin D receptor, or the GATA factors are expressed specifically in atria or ventricles. The finding that Irx4, an Iroquois homeobox gene expressed exclusively in the ventricles during embryonic and postnatal heart development (36), is recruited to the VDRE through its physical interaction with RXRα and inhibits expression of the MyHC3 promoter (37), provides one mechanism for spatial restriction of gene ex-
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Figure 1. A model for chamber-specific expression of the quail slow myosin heavy chain promoter type 2 (MyHC3). a) In atria, GATA proteins ensure the expression of the promoter via their activation domains and possible interaction with a cofactor. b) In ventricles, the vitamin D (VDR)/retinoic acid receptor (RXR) heterodimer interacts with the Iroquois homeobox protein Irx4 present only in ventricles to repress the expression of the promoter possibly by blocking access to the promoter of coactivators.
Figure 2. Schematic representation of the rat ANF promoter. a) The rat ANF –700 bp promoter harbours three regulatory modules responsible for its basal, atrial, and ventricular expression in cardiomyocytes. Specific elements are also depicted. GATA elements, Nkx2.5 binding sites (NKE), SRF binding sites (SRE), Tbx binding sites (TBE), A/T-rich element, PERE (phenylephrine response element), CARE (cardiac restricted element), TRE (thyroid hormone response element). b) Putative cardiac-specific transcription complex assembled over the ANF proximal promoters can be deduced from existing data. CBP, CREB binding proteins; GTF machinery, general transcription factor machinery).
pression (Fig 1). Given that Irx4 is not detectably present in ventricles prior to mouse embryonic d8 (36), this mechanism of achieving chamber-specific expression as a consequence of transcriptional repression may be relevant to cardiac genes whose expression becomes spatially restricted at later stages of heart development. Analysis of atrial-specific expression of the ANF promoter led to the identification of two regulatory domains that displayed atrial-specific activity. The first was found within the proximal promoter and mapped to the NKE; although the activity of the isolated NKE was similar in atria and ventricles, its mutation in the context of the native ANF promoter reduced promoter activity in a chamber-specific manner (4); this finding suggested that other elements (and their cognate binding proteins) interact with the NKE to restrict its activity to atria. One candidate was the upstream promoter region between –200 and –380 bp which contains three regulatory elements: CARE, a binding site for a novel transcription factor containing a bona fide helicase (39) that acts as a stage-specific enhancer that is active preferentially in embryonic not postnatal myocyte where its activity is higher in atria versus ventricles; a GATA element with higher affinity for GATA-4 versus GATA-6 (27) but with no differential chamber activity; and finally, a
composite element containing juxtaposed binding sites for Nkx2.5 and T-box containing transcription factors, which was required for maximal atrial but not ventricular promoter activity (Fig 2a). The finding that Tbx5, a member of the T-box family of transcription factors implicated in the Holt– Oram syndrome, has a pattern of expression similar to that of ANF, prompted the study of the regulation of the ANF promoter by Tbx5 and the possible interaction of Tbx5 with Nkx2.5 to achieve atrial specificity. The studies revealed that the ANF promoter harbours three T-box elements (TBEs) that bind with high affinity to Tbx5 and is potently activated by Tbx5 in cotransfection assays (38). In vivo inactivation of the Tbx5 gene confirmed that ANF and connexin-40 are in vivo targets for Tbx5 (38). In addition, Tbx5 null embryos showed severe hypoplasia of the atria consistent with a role for Tbx5 in the earliest steps of cardiac segmentation (38). Interestingly, Tbx5 and Nkx2.5 physically interact and synergistically activate at least two atrial-specific promoters, ANF and connexin-40. This cooperative interaction is among the strongest between members of two different classes of transcription factors as both proteins can form a stable ternary complex on a DNA sequence harbouring binding sites for both transcription factors. Both DNA binding domains are
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involved in the interaction, whereas the transcriptional activation domains of both proteins are required for the synergy (38, 40). In addition to the implication of both transcription factors in chamber specification, the finding that they interact to activate the connexin40 promoter suggests an even wider role in controlling the development and function of the cardiac conduction system. Also, the similar phenotypes, ie cardiac septal defects encountered in human mutations of either one of the two genes (41, 42), strengthens the relevance of the converging pathways of both proteins.
Cardiac hypertrophy One of the features of the adult cardiomyocyte is its withdrawal from the cell cycle and thus its inability to proliferate. Instead, it responds to growth factors and hormones by increasing cell size leading to cardiac hypertrophy. A genetic reprogramming that results in re-induction of fetal genes characterizes hypertrophied myocytes. Many signalling pathways are involved in the transduction of hypertrophic stimuli to the nucleus. These include the calmodulin kinase pathway, the calcineurin pathway, and the MAPK pathway (43), which converge on a subset of transcription factors. The ANF response elements for endothelin stimulation have been mapped to the juxtaposed GATA and SRE sites present in the proximal promoter (44). GATA-4 and SRF cooperatively activate ANF and other hypertrophy-induced cardiac promoters including α skeletal actin and α myosin heavy chain (44, 45). In vitro pull-down assays and in vivo coimmunoprecipitation assays show that SRF physically interact with the cardiac-enriched GATA factors to form a stable ternary complex; this complex is enhanced after stimulation with endothelin-1 and may thus account for the increased expression of ANF and other endothelin-1-inducible genes. In T cells, it was shown that activation of the calcineurin pathway leads to dephosphorylation and subsequent nuclear translocation of the transcription factor NF-AT3 (nuclear factor of activated T-cells). Ubiquitously expressed, NF-AT3 is also implicated in cardiac hypertrophy through its interaction with GATA-4, which results in robust cooperative activation of target genes including BNP (46, 47). Finally, it is worth noting that the GATA/MEF2 interaction may also be relevant to genetic reprogramming in cardiac hypertrophy as both GATA-4 and MEF2 are
the targets of post-translational modifications by MAPK pathways leading to their activation (48). Whether these modifications modulate GATA-4 interactions with any of its partners will be interesting to assess.
Conclusion Much knowledge has been learned concerning regulation of cardiac genes through mutational analysis of cardiac promoter sequences in vitro and in vivo. However, the existence of multiple protein complexes involved in the basal and pathophysiological regulation of these genes makes it difficult at present to conclude on their individual role in vivo. The differential pathways involved in the spatial and developmental expression of ANF illustrate well the complexity of the regulatory networks involved in heart function (Fig 2). Two important avenues will need to be explored further to elucidate the mechanisms regulating combinatorial interactions at different stages of cardiac development and disease. One involves analysis of post-translational regulation of each protein in a given complex and its effect on complex assembly and function; acetylation/desacetylation as well as phosphorylation/dephosphorylation events are probable key regulatory mechanisms that modulate activity of many transcription factors in different cellular contexts such as proliferation, differentiation, and apoptosis. In parallel, mapping of the protein–protein interfaces implicated in different interactions may provide means of interfering with specific interactions at different stages of cardiomyocyte function. It would also allow generation of animal models harbouring mutations that will disrupt specific interactions (through knockin approaches) thus allowing in vivo assessment of multiprotein complexes. This will pave the way for designing new pharmacological tools that will target specific interactions implicated in cardiovascular diseases. The authors acknowledge the invaluable contributions of all the present and past members of the laboratory who have contributed to our current understanding of cardiac transcription as well as the expert secretarial help of Mrs Lise Laroche. Work performed in our laboratory was supported by grants from The Canadian Institutes of Health Research (CIHR), The Heart and Stroke Foundation of Canada (HSFC), and The Cancer Research Society. Dr M Nemer is a senior CIHR Scientist and holds a Canada Chair in Molecular Biology.
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