ArticleDevelopmental biology2013
Spatiotemporal regulation of an Hcn4 enhancer defines a role for Mef2c and HDACs in cardiac electrical patterning.
Article in Developmental biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Cardiac conduction system malformations in heterotaxy result from dysregulated Pitx2 expression.JCI insight · 2026Article
- Enhancer Trajectories in Lineage Commitment: Regulatory Logic of States and Cooperation.Biomolecules · 2026Review
- The role of P21-activated kinase (Pak1) in sinus node function.Journal of molecular and cellular cardiology · 2023Article
- Global chromatin landscapes identify candidate noncoding modifiers of cardiac rhythm.The Journal of clinical investigation · 2023Article
- Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models.American journal of human genetics · 2022Article
- Heart failure in mice induces a dysfunction of the sinus node associated with reduced CaMKII signaling.The Journal of general physiology · 2022Article
- A dualiScience · 2022Article
- Transcriptional and Epigenetic Landscape of Cardiac Pacemaker Cells: Insights Into Cellular Specialization in the Sinoatrial Node.Frontiers in physiology · 2021Review
- ATAC-Seq Reveals anCirculation research · 2020Article
- Premature MicroRNA-1 Expression Causes Hypoplasia of the Cardiac Ventricular Conduction System.Frontiers in physiology · 2019Article
- Precardiac organoids form two heart fields via Bmp/Wnt signaling.Nature communications · 2018Article
- The transcription factor MEF2A fine-tunes gene expression in the atrial and ventricular chambers of the adult heart.The Journal of biological chemistry · 2017Article
- On the Evolution of the Cardiac Pacemaker.Journal of cardiovascular development and disease · 2017Review
- Familial inappropriate sinus tachycardia: a new chapter in the story of HCN4 channelopathies.European heart journal · 2017Article
- New Approaches to Biological Pacemakers: Links to Sinoatrial Node Development.Trends in molecular medicine · 2015Review
- A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaker cell fate in the pulmonary vein myocardium and sinoatrial node.Development (Cambridge, England) · 2015Article
- The short stature homeobox 2 (Shox2)-bone morphogenetic protein (BMP) pathway regulates dorsal mesenchymal protrusion development and its temporary function as a pacemaker during cardiogenesis.The Journal of biological chemistry · 2015Article
- Insights into cardiac conduction system formation provided by HCN4 expression.Trends in cardiovascular medicine · 2015Review
- GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development.Nature communications · 2014Article
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4 authors.
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Abstract
Regional differences in cardiomyocyte automaticity permit the sinoatrial node (SAN) to function as the leading cardiac pacemaker and the atrioventricular (AV) junction as a subsidiary pacemaker. The regulatory mechanisms controlling the distribution of automaticity within the heart are not understood. To understand regional variation in cardiac automaticity, we carried out an in vivo analysis of cis-regulatory elements that control expression of the hyperpolarization-activated cyclic-nucleotide gated ion channel 4 (Hcn4). Using transgenic mice, we found that spatial and temporal patterning of Hcn4 expression in the AV conduction system required cis-regulatory elements with multiple conserved fragments. One highly conserved region, which contained a myocyte enhancer factor 2C (Mef2C) binding site previously described in vitro, induced reporter expression specifically in the embryonic non-chamber myocardium and the postnatal AV bundle in a Mef2c-dependent manner in vivo. Inhibition of histone deacetylase (HDAC) activity in cultured transgenic embryos showed expansion of reporter activity to working myocardium. In adult animals, hypertrophy induced by transverse aortic constriction, which causes translocation of HDACs out of the nucleus, resulted in ectopic activation of the Hcn4 enhancer in working myocardium, recapitulating pathological electrical remodeling. These findings reveal mechanisms that control the distribution of automaticity among cardiomyocytes during development and in response to stress.
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