RNA sequencing of mouse sinoatrial node reveals an upstream regulatory role for Islet-1 in cardiac pacemaker cells.

Rationale: Treatment of sinus node disease with regenerative or cell-based therapies will require a detailed understanding of gene regulatory networks in cardiac pacemaker cells (PCs).

Objective: To characterize the transcriptome of PCs using RNA sequencing and to identify transcriptional networks responsible for PC gene expression.

Methods And Results: We used laser capture microdissection on a sinus node reporter mouse line to isolate RNA from PCs for RNA sequencing. Differential expression and network analysis identified novel sinoatrial node-enriched genes and predicted that the transcription factor Islet-1 is active in developing PCs. RNA sequencing on sinoatrial node tissue lacking Islet-1 established that Islet-1 is an important transcriptional regulator within the developing sinoatrial node.

Conclusions: (1) The PC transcriptome diverges sharply from other cardiomyocytes; (2) Islet-1 is a positive transcriptional regulator of the PC gene expression program.