The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart

Hoogaars, Willem M.H.; Tessari, Alessia; Moorman, Antoon F.M.; Boer, Piet A. J. de; Hagoort, Jaco; Soufan, Alexandre T.; Campione, Marina; Christoffels, Vincent M.

doi:10.1016/j.cardiores.2004.01.030

Cited by 302 publications

(184 citation statements)

References 41 publications

(47 reference statements)

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“…It has been shown that Tbx5 synergistically interacts with Nkx2.5 in the activation of the ANF regulatory element, responsible for expression of Anf in the cardiac chambers [9]. A similar regulatory element, composed of TBE and NKE binding sites, has been found in the promoters of other chamber-specific genes, such as Cx40 and Cx43 [10]. The lack of expression of chamber specific genes in non-chamber myocardium has been attributed to the expression of Tbx2 which is mutually exclusive with that of chamber myocardium markers [11].…”

Section: Introductionmentioning

confidence: 93%

“…Tbx3 is co-expressed with Tbx2 in the heart in looping stages and biochemical studies suggest Tbx3, like Tbx2, is capable of repressing transcription from the ANF element in chamber specific genes [10]. In humans, haploinsufficiency of TBX3 causes the Ulnar Mammary syndrome (UMS), a pleiotropic disorder that typically presents defects in limb, mammary gland, tooth, hair and apocrine gland development [23].…”

Section: Introductionmentioning

confidence: 99%

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Tbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling

et al. 2007

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BackgroundThe heart forms from a linear tube that is subject to complex remodeling during embryonic development. Hallmarks of this remodeling are the looping of the heart tube and the regionalization into chamber and non-chamber myocardium. Cardiomyocytes in the future chamber myocardium acquire different cellular and physiological characteristics through activation of a chamber-specific genetic program, which is in part mediated by T-box genes.Methodology/Principal FindingWe characterize two new zebrafish T-box transcription factors, tbx3b and tbx2a, and analyze their role during the development of the atrioventricular canal. Loss- and gain-of-function analyses demonstrate that tbx3b and tbx2a are necessary to repress the chamber-genetic program in the non-chamber myocardium. We also show that tbx3b and tbx2a are required to control cell proliferation in the atrioventricular canal and that misregulation of cell proliferation in the heart tube influences looping. Furthermore, we characterize the heart phenotype of a novel Tbx3 mutation in mice and show that both the control of cell proliferation and the repression of chamber-specific genetic program in the non-chamber myocardium are conserved roles of Tbx3 in this species.Conclusions/SignificanceTaken together, our results uncover an evolutionarily conserved role of Tbx2/3 transcription factors during remodeling of the heart myocardium and highlight the importance of controlling cell proliferation as a driving force of morphogenesis.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Tbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling

et al. 2007

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“…Reduced expression of TBX3 in proximal bundle branches is associated with greater expression of connexins 40 and 43, and accordingly, faster conduction,47 which is manifest by shorter QRS duration. TBX3 deficiency can also lead to insufficient development of AVN,46 which might manifest as prolonged PR interval. Indeed, supporting this connection between QRS and PR interval, the GWAS variant associated with increased QRS interval is also associated with decreased PR interval 42, 43.…”

Section: Discussionmentioning

confidence: 99%

Genome‐Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study)

Tereshchenko

Sotoodehnia

Sitlani

et al. 2018

JAHA

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Background ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome‐wide association study would identify genetic loci related to GEH.Methods and ResultsWe tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS‐T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12‐lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome‐wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near TBX3) was associated with QRS‐T angle (white standardized β+0.16 [95% CI 0.13–0.19]; P=1.5×10−26), spatial ventricular gradient elevation (+0.11 [0.08–0.14]; P=2.1×10−12), and spatial ventricular gradient magnitude (−0.12 [95% CI −0.15 to −0.09]; P=5.9×10−15). Altogether, GEH‐SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near HMCN2), 5 (IGF1R), 11 (11p11.2 region cluster), and 7 (near ACTB) are novel ECG phenotype‐associated loci. Several loci significantly associated with gene expression in the left ventricle (HMCN2 locus—with HMCN2;IGF1R locus—with IGF1R), and atria (RP11‐481J2.2 locus—with expression of a long non‐coding RNA and NDRG4).ConclusionsWe identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH‐loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.

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“…Multiple transcriptional repressors have been show to influence formation and function of the conduction system. For example, Tbx2 and Tbx3 are expressed within the central conduction system to repress working cardiomyocyte-specific genes (11,12). To accomplish this function, they interact with Nkx2.5 and prevent transcriptional activation of the chamber-specific genes Nppa and Cx43 to reinforce conduction cell identity.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, while Tbx5 and Nkx2.5 are expressed broadly within the developing heart to activate transcription, the inhibitory T-box transcription factors Tbx2 and Tbx3 are confined to AV node progenitor cells and repress working cardiomyocyte-specific genes (i.e., Nppa and Cx43) by antagonizing Nkx2.5 (11)(12)(13)(14)(15). In addition, well-characterized signaling pathways influence these transcriptional mechanisms to refine AVN morphogenesis.…”

mentioning

confidence: 99%

MyoR Modulates Cardiac Conduction by Repressing Gata4

Harris

Bhakta

Bezprozvannaya

et al. 2015

Molecular and Cellular Biology

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The cardiac conduction system coordinates electrical activation through a series of interconnected structures, including the atrioventricular node (AVN), the central connection point that delays impulse propagation to optimize cardiac performance. Although recent studies have uncovered important molecular details of AVN formation, relatively little is known about the transcriptional mechanisms that regulate AV delay, the primary function of the mature AVN. We identify here MyoR as a novel transcription factor expressed in Cx30.2 ؉ cells of the AVN. We show that MyoR specifically inhibits a Cx30.2 enhancer required for AVN-specific gene expression. Furthermore, we demonstrate that MyoR interacts directly with Gata4 to mediate transcriptional repression. Our studies reveal that MyoR contains two nonequivalent repression domains. While the MyoR C-terminal repression domain inhibits transcription in a context-dependent manner, the N-terminal repression domain can function in a heterologous context to convert the Hand2 activator into a repressor. In addition, we show that genetic deletion of MyoR in mice increases Cx30.2 expression by 50% and prolongs AV delay by 13%. Taken together, we conclude that MyoR modulates a Gata4-dependent regulatory circuit that establishes proper AV delay, and these findings may have wider implications for the variability of cardiac rhythm observed in the general population.

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The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart

Cited by 302 publications

References 41 publications

Tbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling

Tbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling

Genome‐Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study)

MyoR Modulates Cardiac Conduction by Repressing Gata4

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