The role of alternative promoter usage in tissue-specific gene expression has been well established; however, its role in complex diseases is poorly understood. We performed cap analysis of gene expression (CAGE) sequencing from the left ventricle of a rat model of hypertension, the spontaneously hypertensive rat (SHR), and a normotensive strain, Brown Norway to understand the role of alternative promoter usage in complex disease. We identified 26,560 CAGE-defined transcription start sites in the rat left ventricle, including 1,970 novel cardiac transcription start sites. We identified 28 genes with alternative promoter usage between SHR and Brown Norway, which could lead to protein isoforms differing at the amino terminus between two strains and 475 promoter switching events altering the length of the 5' UTR. We found that the shift in Insr promoter usage was significantly associated with insulin levels and blood pressure within a panel of HXB/BXH recombinant inbred rat strains, suggesting that hyperinsulinemia due to insulin resistance might lead to hypertension in SHR. Our study provides a preliminary evidence of alternative promoter usage in complex diseases.

Cardiovascular and Metabolic Sciences Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany

Charité Universitätsmedizin Berlin Germany

Department of Metabolism Digestion and Reproduction Faculty of Medicine Imperial College London London UK

Department of Microbial Sciences Faculty of Health and Medical Sciences University of Surrey Guildford UK

DZHK Partner Site Berlin Berlin Germany

Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Princess Máxima Center for Pediatric Oncology Utrecht Netherlands

The National Institute for Health Research Imperial Biomedical Research Centre ITMAT Data Science Group Imperial College London London UK

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