Vasanth Vedantham1, Giselle Galang1, Melissa Evangelista1, Rahul C Deo2, Deepak Srivastava2. 1. From the Gladstone Institute of Cardiovascular Disease, San Francisco, CA (V.V., G.G., M.E., D.S.); and Division of Cardiology, Departments of Medicine (V.V., G.G., R.C.D.), Pediatrics (D.S.), and Biochemistry and Biophysics (R.C.D., D.S.), Institute for Human Genetics, California Institute for Quantitative Biosciences (R.C.D.), and Cardiovascular Research Institute (V.V., G.G., M.E., R.C.D.), University of California, San Francisco. 2. From the Gladstone Institute of Cardiovascular Disease, San Francisco, CA (V.V., G.G., M.E., D.S.); and Division of Cardiology, Departments of Medicine (V.V., G.G., R.C.D.), Pediatrics (D.S.), and Biochemistry and Biophysics (R.C.D., D.S.), Institute for Human Genetics, California Institute for Quantitative Biosciences (R.C.D.), and Cardiovascular Research Institute (V.V., G.G., M.E., R.C.D.), University of California, San Francisco. Vasanth.Vedantham@ucsf.edu Rahul.Deo@ucsf.edu.
Abstract
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.
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.
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