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Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 28, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp171
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

The cardiac pacemaker specific channel Hcn4 is a direct transcriptional target of MEF2

Shinobu Kuratomi1, Yoko Ohmori1, Masayuki Ito1, Kuniko Shimazaki1, Shin-ichi Muramatsu2, Hiroaki Mizukami3, Hideki Uosaki4, Jun Yamashita4, Yuji Arai5, Koichiro Kuwahara6 and Makoto Takano1

1 Department of Physiology, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498 Japan
2 Division of Neurology, Department of Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498 Japan
3 Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498 Japan
4 Laboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507 Japan
5 Department of Bioscience, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565 Japan
6 Department of Medicine and Clinical Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8507 Japan.

correspondence author; Makoto Takano, Department of Physiology, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498 Japan, Tel: +81-285-58-7308; Fax: +81-285-40-6294, E-mail: takanom{at}jichi.ac.jp

Aims: Hcn4, which encodes the hyperpolarization-activated, cyclic nucleotide-sensitive channel (Ih), is a well-established marker of the cardiac sino-atrial node. We aimed to identify cis-elements in the genomic locus of the Hcn4 gene that regulate the transcription of Hcn4.

Methods and Results: We screened evolutionarily conserved non-coding sequences (CNSs) that are often involved in the regulation of gene expression. The VISTA Enhancer Browser identified 16 regions, termed CNS 1-16, within the Hcn4 locus. Using the luciferase reporter assay in primary neonatal rat cardiomyocytes, we found that CNS13 conferred a prominent enhancer activity (> 30-fold) on the Hcn4 promoter. Subsequent mutation analysis revealed that the Hcn4 enhancer function was dependent on myocyte enhancer factor-2 (MEF2) and activator protein-1 (AP1) binding sequences located in CNS13. Electrophoretic mobility shift assay and chromatin immunoprecipitation confirmed that MEF2 and AP1 proteins bound CNS13. Furthermore, overexpression of a dominant negative MEF2 mutant inhibited the enhancer activity of CNS13, decreased Hcn4 mRNA expression and also decreased the amplitude of Ih current in myocytes isolated from the inflow tract of embryonic heart.

Conclusions: These results suggest that the novel enhancer CNS13 and MEF2 may play a critical role in the transcription of Hcn4 in the heart.

Time for primary review: 34 Days


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