Abstract
The hyperpolarization-activated cation channel (HCN4) shows differential expression patterns during the embryonic development and hypertrophy of hearts. Briefly, HCN4 expression is maximally activated in embryonic hearts and quickly diminishes after birth. However, its expression is reactivated during cardiac hypertrophy. The sequence analysis of the HCN4 gene revealed the presence of a conserved neuron-restrictive silencer element (NRSE). NRSE is known to bind neuron-restrictive silencing factor (NRSF). We initiated the characterization of the 5' promoter region of the HCN4 gene. A promoter truncation analysis with cardiac myocytes revealed the -446/+400 promoter region that induced a basal transcriptional activity. This region drove a high transcriptional activity in embryonic myocytes, but not in neonatal myocytes treated with hypertrophic agents. After confirming that NRSF binds to the intronic NRSE and represses HCN4 promoter, transcriptional activities modified by wild-type or mutated NRSE were evaluated. With wild-type NRSE, HCN4 promoter activity correlated well with the expression patterns, whereas mutant constructs failed to induce such transcriptional activity. These findings demonstrate that the release of transcriptional repression mediated by NRSF is required for the upregulation of HCN4 expression with cardiac myocyte hypertrophy. We conclude that the NRSE-NRSF regulatory system was implicated in HCN4 expression during the development and hypertrophy of cardiac myocytes. [J Physiol Sci. 2007;57 Suppl:S203]
