Identifying the Evolutionary Building Blocks of the Cardiac Conduction System

Jensen, Bjarke; Boukens, Bastiaan J.; Postma, Alex V.; Gunst, Quinn D.; Hoff, Maurice J.B. van den; Moorman, Antoon F.M.; Wang, Tobias; Christoffels, Vincent M.

doi:10.1371/journal.pone.0044231

Cited by 102 publications

(133 citation statements)

References 80 publications

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“…44 The atrioventricular canal component is evolutionarily conserved in vertebrates. 45 Our data reveal that the regulatory sequences regulating Tbx3 in these respective components are separated in the genome and suggest that eA is responsible for driving Tbx3 expression in the conserved AVC component through a BMP signaling-mediated mechanism. Although on its own weak, eB seems to synergize with eA to drive robust Tbx3 expression in the AVC and atrioventricular bundle precursor region in the interventricular septum.…”

Section: Discussionmentioning

confidence: 71%

A Large Permissive Regulatory Domain Exclusively Controls Tbx3 Expression in the Cardiac Conduction System

Weerd

Badi

Boogaard

et al. 2014

Circulation Research

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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 and mouse. Both genes are expressed in overlapping patterns and function in strictly tissue-specific and dose-dependent manners, yet, their regulation is poorly understood. Objective : To analyze the mechanism underlying the complex regulation of the Tbx3 / Tbx5 cluster. Methods and Results : By probing the 3-dimensional architecture of the Tbx3/Tbx5 cluster using high-resolution circular chromosome conformation capture sequencing in vivo, we found that its regulatory landscape is in a preformed conformation similar in embryonic heart, limbs, and brain. Tbx3 and its flanking gene desert form a 1 Mbp loop between CCCTC-binding factor (CTCF)-binding sites that is separated from the neighboring Tbx5 loop. However, Ctcf inactivation did not result in transcriptional regulatory interaction between Tbx3 and Tbx5 . Multiple sites within the Tbx3 locus contact the promoter, including sites corresponding to regions known to contain variations in the human genome influencing conduction. We identified an atrioventricular-specific enhancer and a pan-cardiac enhancer that contact the promoter and each other and synergize to activate transcription in the atrioventricular conduction system. Conclusions : We provide a high-resolution model of the 3-dimensional structure and function of the Tbx3 / Tbx5 locus and show that the locus is organized in a preformed, permissive structure. The Tbx3 locus forms a CTCF-independent autonomous regulatory domain with multiple combinatorial regulatory elements that control the precise pattern of Tbx3 in the cardiac conduction system.

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Section: Discussionmentioning

confidence: 71%

A Large Permissive Regulatory Domain Exclusively Controls Tbx3 Expression in the Cardiac Conduction System

Weerd

Badi

Boogaard

et al. 2014

Circulation Research

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“…Previous ZF optical reports have placed particular emphasis on the conduction patterns in the embryonic or adult ZF ventricle (24,25,34,38), while our study focused more on electrophysiological parameters and their sensitivities to acute cooling. Combining all of the AP cycles within a 20-s period is a novelty not present in previous ZF optical mapping reports (34,38) and produced AP traces with an enhanced signal quality, comparable to those found with microelectrode (33) and isolated cell (5) techniques.…”

Section: Discussionmentioning

confidence: 99%

Optical mapping of the electrical activity of isolated adult zebrafish hearts: acute effects of temperature

Lin

Ribeiro

Ding

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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The zebrafish (Danio rerio) has emerged as an important model for developmental cardiovascular (CV) biology; however, little is known about the cardiac function of the adult zebrafish enabling it to be used as a model of teleost CV biology. Here, we describe electrophysiological parameters, such as heart rate (HR), action potential duration (APD), and atrioventricular (AV) delay, in the zebrafish heart over a range of physiological temperatures (18-28°C). Hearts were isolated and incubated in a potentiometric dye, RH-237, enabling electrical activity assessment in several distinct regions of the heart simultaneously. Integration of a rapid thermoelectric cooling system facilitated the investigation of acute changes in temperature on critical electrophysiological parameters in the zebrafish heart. While intrinsic HR varied considerably between fish, the ex vivo preparation exhibited impressively stable HRs and sinus rhythm for more than 5 h, with a mean HR of 158 ± 9 bpm (means ± SE; n = 20) at 28°C. Atrial and ventricular APDs at 50% repolarization (APD50) were 33 ± 1 ms and 98 ± 2 ms, respectively. Excitation originated in the atrium, and there was an AV delay of 61 ± 3 ms prior to activation of the ventricle at 28°C. APD and AV delay varied between hearts beating at unique HRs; however, APD and AV delay did not appear to be statistically dependent on intrinsic basal HR, likely due to the innate beat-to-beat variability within each heart. As hearts were cooled to 18°C (by 1°C increments), HR decreased by ~40%, and atrial and ventricular APD50 increased by a factor of ~3 and 2, respectively. The increase in APD with cooling was disproportionate at different levels of repolarization, indicating unique temperature sensitivities for ion currents at different phases of the action potential. The effect of temperature was more apparent at lower levels of repolarization and, as a whole, the atrial APD was the cardiac parameter most affected by acute temperature change. In conclusion, this study describes a preparation enabling the in-depth analysis of transmembrane potential dynamics in whole zebrafish hearts. Because the zebrafish offers some critical advantages over the murine model for cardiac electrophysiology, optical mapping studies utilizing zebrafish offer insightful information into the understanding and treatment of human cardiac arrhythmias, as well as serving as a model for other teleosts.

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“…5A), these 'lower' endothermic vertebrates do not develop a massive Cx40-negative compact ventricular wall. As such, the trabecular myocardium is also likely to be the evolutionary precursor of the Purkinje fibre system of the endotherms (Jensen et al, 2012).…”

Section: Development Of the Ventricular Conduction Systemmentioning

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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Identifying the Evolutionary Building Blocks of the Cardiac Conduction System

Cited by 102 publications

References 80 publications

A Large Permissive Regulatory Domain Exclusively Controls Tbx3 Expression in the Cardiac Conduction System

A Large Permissive Regulatory Domain Exclusively Controls Tbx3 Expression in the Cardiac Conduction System

Optical mapping of the electrical activity of isolated adult zebrafish hearts: acute effects of temperature

The formation and function of the cardiac conduction system

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