Key result
The Tbx3 locus forms a CTCF-independent autonomous regulatory domain with multiple combinatorial regulatory elements that control its precise expression pattern in the cardiac conduction system.
This study provides a high-resolution 3D model of the Tbx3/Tbx5 locus, revealing a CTCF-independent autonomous regulatory domain that controls Tbx3 expression in the cardiac conduction system.
No immediate clinical implications; leaves open Tbx3 enhancer targeting in human conduction disorders.
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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Weerd et al. (2014) studied Cardiac conduction system development and homeostasis. Ctcf inactivation and 3D chromosome conformation capture was evaluated on 3-dimensional architecture and regulatory landscape of the Tbx3/Tbx5 cluster. The Tbx3 locus forms a CTCF-independent autonomous regulatory domain with multiple combinatorial regulatory elements that control its precise expression pattern in the cardiac conduction system.
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