Cardiac Tissue Enriched Factors Serum Response Factor and GATA-4 Are Mutual Coregulators

Dietary vitamin A and its derivatives, retinoids, regulate cardiac growth and development. To delineate mechanisms involved in retinoid-mediated control of cardiac gene expression, the regulatory effects of the retinoid X receptor ␣ (RXR␣) on atrial naturietic factor (ANF) gene transcription was investigated. The transcriptional activity of an ANF promoter-reporter in rat neonatal ventricular myocytes was repressed by RXR␣ in the presence of 9-cis-RA and by the constitutively active mutant RXR␣F318A indicating that liganded RXR confers the regulatory effect. The RXR␣-mediated repression mapped to the proximal 147 bp of the rat ANF promoter, a region lacking a consensus retinoid response element but containing several known cardiogenic cis elements including a well characterized GATA response element. Glutathione S-transferase "pulldown" assays revealed that RXR␣ interacts directly with GATA-4, in a ligand-independent manner, via the DNA binding domain of RXR␣ and the second zinc finger of GATA-4. Liganded RXR␣ repressed the activity of a heterologous promoter-reporter construct containing GATA-response element recognition sites in cardiac myocytes but not in several other cell types, suggesting that additional cardiac-enriched factors participate in the repression complex. Co-transfection of liganded RXR␣ and the known cardiac-enriched GATA-4 repressor, FOG-2, resulted in additive repression of GATA-4 activity in ventricular myocytes. In addition, RXR␣ was found to bind FOG-2, in a 9-cis-RA-dependent manner. These data reveal a novel mechanism by which retinoids regulate cardiogenic gene expression through direct interaction with GATA-4 and its co-repressor, FOG-2.Retinoids are compounds, derived from vitamin A, which exert pleiotropic effects on cellular differentiation, morphogenesis, and metabolism. The effects of retinoids on cardiac growth and development are well recognized. Offspring of rodents and birds fed a vitamin A-deficient diet display congenital defects involving many organ systems including the cardiovascular system (1, 2). Vitamin A replacement at different stages of embryonic development in these animals actually alters the severity and type of heart defects seen at birth indicating that retinoid signaling pathways play key roles in a variety of developmental programs (1). Similarly, retinaldehyde dehydrogenase-deficient mice die in utero at embryonic day 8 secondary to poor maturation of the ventricular myocardium, an effect that can be rescued by supplementation of maternal vitamin A (3, 4). In addition, retinoids can exert teratogenic effects. Human offspring born of mothers who ingested isotretinoin, a vitamin A analog, during pregnancy exhibited a high incidence of complex cardiac malformations including transposition of the great vessels, tetralogy of Fallot, hypoplastic aortic arch, and ventricular septal defects (5). Moreover, in the developing chick, local application of high concentrations of retinoic acid disrupts the migration of the pre-cardiac mesoderm, an effect that is dose-depe...

Section: Discussionmentioning

confidence: 98%

Retinoid X Receptor α Represses GATA-4-mediated Transcription via a Retinoid-dependent Interaction with the Cardiac-enriched Repressor FOG-2

Clabby

Robison

Quigley³

et al. 2003

“…Paradoxically, SRF was also found to regulate expression of several muscle genes, which are expressed specifically in postmitotic myocytes (2). SRF acts through binding as a homodimer to the DNA consensus sequence CC(A/T) 6 GG, the serum response element (SRE), also referred as the CArG box, which is found essential for tissuespecific expression of numerous striated as well as smooth muscle-specific genes (2,3).…”

mentioning

confidence: 99%

“…SRF has the ability to physically interact and synergistically cooperate with many other known cardiac-myogenic factors, such as GATA-4, Nkx2.5, TEF-1, myocardin, and CRP1/2 (6 -10). Functionally relevant CArG boxes in the promoter regions of several cardiac-restricted, contractile, Ca 2ϩ -transporting, and metabolic protein genes have been identified, indicating a direct role of SRF in their transcriptional regulation (6,11,12). A large body of evidence also indicates that SRF-containing complexes are the end point targets in pathways associated with conversion of hypertrophic stimuli to cardiac cellular response (e.g.…”

mentioning

confidence: 99%

Calcium/Calmodulin-dependent Protein Kinase Activates Serum Response Factor Transcription Activity by Its Dissociation from Histone Deacetylase, HDAC4

Davis

Gupta

Camoretti-Mercado

et al. 2003

Self Cite

116

Serum response factor (SRF) plays a pivotal role in cardiac myocyte development, muscle gene transcription, and hypertrophy. Previously, elevation of intracellular levels of Ca 2؉ was shown to activate SRF function without involving the Ets family of tertiary complex factors through an unknown regulatory mechanism. Here, we tested the hypothesis that the chromatin remodeling enzymes of class II histone deacetylases (HDAC4) regulate SRF activity in a Ca 2؉ -sensitive manner. Expression of HDAC4 profoundly repressed SRFmediated transcription in both muscle and nonmuscle cells. Protein interaction studies demonstrated physical association of HDAC4 with SRF in living cells. The SRF/ HDAC4 co-association was disrupted by treatment of cells with hypertrophic agonists such as angiotensin-II and a Ca 2؉ ionophore, ionomycin. Furthermore, activation of Ca 2؉ /calmodulin-dependent protein kinase (CaMK)-IV prevented SRF/HDAC4 interaction and derepressed SRF-dependent transcription activity. The SRF⅐HDAC4 complex was localized to the cell nucleus, and the activated CaMK-IV disrupted HDAC4/SRF association, leading to export of HDAC4 from the nucleus and stimulation of SRF transcription activity. Thus, these results identify SRF as a functional interacting target of HDAC4 and define a novel tertiary complex factor-independent mechanism for SRF activation by Ca 2؉ /CaMK-mediated signaling.

“…Activation induced by myocardin (27) is extraordinarily dramatic in comparison with the modest activation induced by the other transcription factors (28,29). The extent of activation induced by Tip60 isoproteins is similar to that of GATA4 -6 and Nkx2.5, especially when the chromodomain is deleted from Tip60␤⌬c.…”

Section: Discussionmentioning

confidence: 91%

Co-activation of Atrial Natriuretic Factor Promoter by Tip60 and Serum Response Factor

Kim

Merlo

Wilson

et al. 2006

Tat-interactive protein 60 (Tip60) is a member of the MYST family of histone acetyltransferases (HATs). In addition to its HAT domain, Tip contains a heterochromatin-associated protein 1-like chromodomain and a zinc finger-like domain. Several alternative splice variants of Tip60 have been characterized, including fulllength Tip60␣, Tip60␤ (which lacks exon V encoded by the Tip60 gene), and Tip55 (which encodes a novel 103-amino-acid C terminus). We report here that isoproteins recognized by a pan-Tip60 antibody are strongly and transiently expressed between embryonic days 8 and 11 in the embryonic mouse myocardium. A functional role for Tip60 isoproteins in cardiac myocyte differentiation is suggested by immunoprecipitation experiments showing that Tip60␣, Tip60␤, and Tip55 can bind serum response factor (SRF) and by transient transfection assessments showing that Tip60 and SRF cooperatively activate the atrial natriuretic factor promoter. Although this combinatorial activity is inhibited by histone deacetylase 7, it was unexpectedly enhanced by point mutation of the HAT domain. Ablation of the chromodomain from Tip60␤ caused derepression. These findings suggest that Tip60 modulates expression of SRF-dependent cardiac genes.Since its discovery in 1996 (1), numerous findings have established Tat-interactive protein 60 kDa (Tip60) 3 as a member of the "MYST" family, an acronym denoting the founding members MOZ, YBF2, SAS2, and Tip60 of the family. Although Tip60 proteins are essential for embryonic development as determined by very early embryolethality resulting from homozygous ablation of the Tip60 gene, 4 the cellular function of its alternatively spliced isoforms as well as of its functional domains is only beginning to be understood. Among possible functions, Tip60 has been implicated in chromatin-remodeling complexes wherein it is required for apoptosis and DNA repair (3), during which it mediates acetylation-dependent exchange of histone H2A.X (4). Several studies utilizing transient transfection analysis have implicated Tip60 in the regulation of gene transcription, although whether it functions as a co-activator or co-repressor appears to be context-dependent. For example, Tip60 co-activates transcription with human immunodeficiency virus-1 Tat (1), androgen receptor (5, 6), and ␤-amyloid precursor protein-Fe65 complex (7). By contrast, Tip60 co-represses transcription with cAMP-response element-binding protein (8), zinc finger E box binding protein (9), and STAT3 (10), which repression is potentiated by histone deacetylase 7 (HDAC7).Several putative functional domains are present in Tip60, all of which are atypical. These include a chromatin organization modifier domain (chromodomain), a zinc finger-like domain, and a histone acetyltransferase (HAT) domain. The HAT domain was recently shown to obligatorily acetylate nucleosomal histones during DNA repair (4); however whether Tip60-mediated histone acetylation is required during transcription is unclear. Little is known about the function of the other do...