T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells

Bakker, M.; Boink, Gerard J.J.; Boukens, Bastiaan J.; Verkerk, Arie O.; Boogaard, Malou van den; Haan, A. Dénise den; Hoogaars, Willem M.H.; Buermans, Henk P.J.; Bakker, Jacques M.T. de; Seppen, Jurgen; Tan, Hanno L.; Moorman, Antoon F.M.; Hoen, Peter A C ‘t; Christoffels, Vincent M.

doi:10.1093/cvr/cvs120

Cited by 133 publications

(115 citation statements)

References 37 publications

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“…However, there are data indicating that Shox2 is a target for Tbx5 that has been implicated in human AF and prolonged PR interval through GWAS studies (31,32). Tbx3 has also been implicated in human PR interval prolongation in GWAS studies (32) and induces pacemaker properties in adult myocardium when misexpressed (33). Other than the novel targets we identified here, miR-17-92 and miR106b-25 have other targets.…”

Section: Discussionmentioning

confidence: 70%

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

109

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The molecular mechanisms underlying atrial fibrillation, the most common sustained cardiac arrhythmia, remain poorly understood. Genome-wide association studies uncovered a major atrial fibrillation susceptibility locus on human chromosome 4q25 in close proximity to the paired-like homeodomain transcription factor 2 (Pitx2) homeobox gene. Pitx2, a target of the left-sided Nodal signaling pathway that initiates early in development, represses the sinoatrial node program and pacemaker activity on the left side. To address the mechanisms underlying this repressive activity, we hypothesized that Pitx2 regulates microRNAs (miRs) to repress the sinoatrial node genetic program. MiRs are small noncoding RNAs that regulate gene expression posttranscriptionally. Using an integrated genomic approach, we discovered that Pitx2 positively regulates miR-17-92 and miR-106b-25. Intracardiac electrical stimulation revealed that both miR-17-92 and miR-106b-25 deficient mice exhibit pacing-induced atrial fibrillation. Furthermore electrocardiogram telemetry revealed that mice with miR-17-92 cardiac-specific inactivation develop prolonged PR intervals whereas mice with miR-17-92 cardiac-specific inactivation and miR-106b-25 heterozygosity develop sinoatrial node dysfunction. Both arrhythmias are risk factors for atrial fibrillation in humans. Importantly, miR-17-92 and miR-106b-25 directly repress genes, such as Shox2 and Tbx3, that are required for sinoatrial node development. Together, to our knowledge, these findings provide the first genetic evidence for an miR loss-of-function that increases atrial fibrillation susceptibility. irregular heart rate | single nucleotide variant | mouse genetics A trial fibrillation (AF), the most common arrhythmia in adult patients, increases in prevalence with age to almost 5% of the population over 65. Patients with AF have an increased risk of stroke, dementia, and heart failure (1). Electrical impulses that are critical for a coordinated, physiologic heartbeat originate in the sinoatrial node (SAN). In AF, abnormal fibrillatory atrial impulses override normal SAN function, with resultant irregular conduction to the ventricles. Many cases of ectopic electrical activity originate in the pulmonary vein (2). Other sites of ectopy include the left atrial posterior wall, superior vena cava, interatrial septum, crista terminalis, and coronary sinus myocardium (3, 4).Multiple approaches have been used to uncover genes that may contribute to the AF phenotype in adult patients. A seminal genome-wide association study (GWAS), subsequently replicated by multiple studies, uncovered a single nucleotide variant (SNV) on human 4q25 that was strongly associated with familial AF (5). Patients with the 4q25 variant exhibited early onset AF that was independent from other risk factors such as hypertension and diabetes, suggesting a novel biologic mechanism involving genes located on chromosome 4q25. The presence of the 4q25 SNV also had prognostic value because patients with the SNV are prone to cardioembolic str...

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Section: Discussionmentioning

confidence: 70%

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

109

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“…3). Ectopic Tbx3 expression leads to the formation of bona fide functional pacemaker cells within these atria Bakker et al, 2012). Tbx3 thus imposes a pacemaker phenotype on cells within its expression domain.…”

Section: Transcriptional Programming Of the Sanmentioning

confidence: 99%

“…Tbx2 and Tbx3 interact with the musclesegment homeobox transcription factor Msx2, which is expressed in the AVC, to suppress the expression of Cx43 directly (Boogerd et al, 2008;Chen et al, 2008). They also compete with Tbx5 both for binding to T-box elements in target genes, such as Nppa and Cx40 (Hoogaars et al, 2004;van den Boogaard et al, 2012) , and for interaction with Nkx2-5 to repress Nppa in the AVC (Habets et al, 2002). Bone morphogenetic protein 2 (Bmp2) is expressed specifically in the embryonic AVC and is required for AVC development, acting to control the AVC-restricted expression of Tbx2 and Tbx3 (Ma et al, 2005;Singh et al, 2012).…”

Section: Transcriptional Regulation Of Avc and Avn Developmentmentioning

confidence: 99%

The formation and function of the cardiac conduction system

2016

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The cardiac conduction system (CCS) consists of distinctive components that initiate and conduct the electrical impulse required for the coordinated contraction of the cardiac chambers. CCS development involves complex regulatory networks that act in stage-, tissue-and dose-dependent manners, and recent findings indicate that the activity of these networks is sensitive to common genetic variants associated with cardiac arrhythmias. Here, we review how these findings have provided novel insights into the regulatory mechanisms and transcriptional networks underlying CCS formation and function.

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“…It is unclear, however, which cardiac subtype is preferentially induced by current protocols or whether a specific cardiac subtype can be directed by a direct reprogramming approach. Thus, we aimed to generate induced PM (iPM) myocytes by forced expression of selected lineage-specifying transcription factors in primary fibroblasts rather than mature atrial or ventricular myocytes (Bakker et al, 2012;Kapoor et al, 2013). As a first step toward this goal, we sought to develop a reliable reporter system that faithfully marks PM cells, thereby allowing us to perform initial large-scale screening experiments.…”

Section: Selected Reprogramming Factors Activate Hcn4 Reporter Expresmentioning

confidence: 99%

Induction of diverse cardiac cell types by reprogramming fibroblasts with cardiac transcription factors

et al. 2014

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Various combinations of cardiogenic transcription factors, including Gata4 (G), Hand2 (H), Mef2c (M) and Tbx5 (T), can reprogram fibroblasts into induced cardiac-like myocytes (iCLMs) in vitro and in vivo. Given that optimal cardiac function relies on distinct yet functionally interconnected atrial, ventricular and pacemaker (PM) cardiomyocytes (CMs), it remains to be seen which subtypes are generated by direct reprogramming and whether this process can be harnessed to produce a specific CM of interest. Here, we employ a PM-specific Hcn4-GFP reporter mouse and a spectrum of CM subtypespecific markers to investigate the range of cellular phenotypes generated by reprogramming of primary fibroblasts. Unexpectedly, we find that a combination of four transcription factors (4F) optimized for Hcn4-GFP expression does not generate beating PM cells due to inadequate sarcomeric protein expression and organization. However, applying strict single-cell criteria to GHMT-reprogrammed cells, we observe induction of diverse cellular phenotypes, including those resembling immature forms of all three major cardiac subtypes (i.e. atrial, ventricular and pacemaker). In addition, we demonstrate that cells induced by GHMT are directly reprogrammed and do not arise from an Nxk2.5 + progenitor cell intermediate. Taken together, our results suggest a remarkable degree of plasticity inherent to GHMT reprogramming and provide a starting point for optimization of CM subtype-specific reprogramming protocols.

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T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells

Cited by 133 publications

References 37 publications

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

The formation and function of the cardiac conduction system

Induction of diverse cardiac cell types by reprogramming fibroblasts with cardiac transcription factors

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