Genome-wide mRNA expression analyses revealed dysregulation of genes important for SAN function in Hcn4-CreERT2;Isl1 mutants.

Understanding factors that drive development and function of the sinoatrial node (SAN) is crucial to development of potential therapies for sinus arrhythmias, including potential generation of biological pacemakers. Here, we identify a key cell autonomous role for the LIM homeodomain transcription factor ISL1 for survival, proliferation and function of pacemaker cells throughout development. Analysis of several Isl1 mutant mouse lines, including one in which Isl1 was specifically ablated in SAN (Hcn4- CreERT2;Isl1) revealed an early requirement for Isl1 within SAN for embryonic viability. RNA-seq analyses on FACS purified SAN cells revealed dysregulation of a number of genes critical for SAN function to be downstream of ISL1 in Hcn4-CreERT2;Isl1 mutants, including transcription factors and ion channels. Our studies demonstrated that ISL1 regulated approximately one third of genes that were significantly expressed in SAN, and highlight the potential for utilization of ISL1 in combination with other SAN transcription factors for generating pacemaker cells for therapy or drug screening purposes. Results also suggest Isl1 as a candidate gene for sick sinus syndrome. Overall design: RNA-seq analyses were performed on samples from Hcn4-CreERT2;Isl1 mutant and control SANs

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Liang X, Zhang Q, Cattaneo P, Zhuang S, Gong X, Spann NJ, Jiang C, Cao X, Zhao X, Zhang X, Bu L, Wang G, Chen HS, Zhuang T, Yan J, Geng P, Luo L, Banerjee I, Chen Y, Glass CK, Zambon AC, Chen J, Sun Y, Evans SM