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Brief Funct Genomics. 2014 Jan;13(1):28-38. doi: 10.1093/bfgp/elt031. Epub 2013 Aug 22.

Gene regulatory elements of the cardiac conduction system.

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Department of Anatomy, Embryology & Physiology, Academic Medical Centre, L2-108, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands. Tel.: + 31 20 5667821; Fax: + 31 20 6976177;


The coordinated contraction of the heart relies on the generation and conduction of the electrical impulse. Aberrations of the function of the cardiac conduction system have been associated with various arrhythmogenic disorders and increased risk of sudden cardiac death. The genetics underlying conduction system function have been investigated using functional studies and genome-wide association studies. Both methods point towards the involvement of ion channel genes and the transcription factors that govern their activity. A large fraction of disease- and trait-associated sequence variants lie within non-coding sequences, enriched with epigenetic marks indicative of regulatory DNA. Although sequence conservation as a result of functional constraint has been a useful property to identify transcriptional enhancers, this identification process has been advanced through the development of techniques such as ChIP-seq and chromatin conformation capture technologies. The role of variation in gene regulatory elements in the cardiac conduction system has recently been demonstrated by studies on enhancers of SCN5A/SCN10A and TBX5. In both studies, a region harbouring a functionally implicated single-nucleotide polymorphism was shown to drive reproducible cardiac expression in a reporter gene assay. Furthermore, the risk variant of the allele abrogated enhancer function in both cases. Functional studies on regulatory DNA will likely receive a boost through recent developments in genome modification technologies.


TBX transcription factors; arrhythmias; cardiac conduction system; enhancers; epigenetic variation; genetic variation

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