SODIUM CHANNEL

Study of the molecular mechanisms that regulate SCN5A expression

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'Sudden cardiac death syndromes are an important cause of mortality in young individuals in developed countries. The SCN5A gene, which encodes the alpha subunit of the cardiac sodium channel, plays a key role in controlling the sodium currents during the action potential. When malfunctioning due to loss-of-function genetic defects, SCN5A may be responsible for lethal diseases like Brugada syndrome or familial conduction disease. However, little is known regarding SCN5A gene expression regulation, both at the transcriptional or posttranscriptional level. In this project I am proposing to further elucidate the molecular mechanisms that regulate the expression of the SCN5A gene. Using in vitro, cell culture and in vivo experimental approaches, I propose to study the following objectives: 1) To characterize the transcription factors implicated in the transcriptional regulation of the SCN5A promoter in cell culture, EMSA and ChIP experiments; 2) To study the role of DNA methylation in SCN5A expression by analyzing the presence of methylated DNA in cardiac cell derived genomic samples from a cohort of individuals; 3) To study the role of microRNAs with putative binding sites at the 3’UTR of the regulatory region of SCN5A to the cardiac sodium channel. We anticipate that these studies will bring new insights and better understanding of promoter regulation and sodium channel expression. Because of the clinical relevance of this cardiac channel in many arrhythmias, we predict that these studies will have an impact for the future diagnosis and treatment of patients with cardiac arrhythmias and sudden cardiac death syndromes.'

Introduzione (Teaser)

Rhythm disturbances in the heartbeat can cause sudden cardiac death. An EU project is investigating the role of a gene that plays a key role in heartbeat rhythm control.

Descrizione progetto (Article)

An electrical impulse triggers contraction of heart muscle. One gene, SCN5A, may be responsible for Brugada's syndrome (BrS), characterised by a slowed or blocked impulse. When working properly, SCN5A starts a rapid sodium current to start the cardiac potential in heart muscle cells, also called cardiomyocytes.

The 'Study of the molecular mechanisms that regulate SCN5A expression' (SODIUM CHANNEL) project is investigating how mutations in SCN5A affect its function. The researchers started by looking at the molecular control of the gene by optimising chromatin immunoprecipitation (ChIP) assays in human cardiac tissue. The ChIP protocol provides information on interaction between DNA and proteins.

Researchers found that GATA-4, a transcription factor known to be important in heart development and function, binds to and activates SCN5A promoter activity. Moreover, the results indicate that GATA-4 is critical for active SCN5A transcription and works with a related transcription factor, GATA-5 to escalate SCN5A promoter activity.

In the last part of the project term, SODIUM CHANNEL will use next generation sequencing to identify new regulatory mechanisms. The researchers expect that the results will contribute to understanding and management of cardiac arrhythmias.