Abstract 372: Master Transcriptional Regulators of Cardiac Gene Expression in Heart Failure

Abstract

Background: Heart failure (HF) is characterized by complex transcriptional networks that direct the heart from a healthy to diseased state. Although some contributing genes have been identified through molecular biology and GWAS, heritability studies suggest that many genes have resisted discovery through these approaches. Identifying connective regulatory loci, especially master transcriptional regulators that affect the expression of many genes, offers a promising means of discovering novel relevant genes that have not been detected with other methods. Methods and Results: Transcriptional regulators of HF were identified using nine-week-old female mice from 93 lines of the Hybrid Mouse Diversity Panel. Mice received 30 ug/g/day of isoproterenol (ISO) for 3 weeks to induce cardiac dysfunction. Transcriptomes were generated from left ventricles of these mice along with age-matched controls. Expression Quantitative Trait Loci (eQTLs) for 13,156 transcripts were identified using a mixed model in three conditions (control, treated, delta). Suggestive (P<1E-4) eQTLs were sorted into 500kb bins tiled across the genome to identify loci that regulate a significant number of transcripts. Ten hotspot loci that regulate over 5% (658 of 13156) of expressed genes were identified, several of which contain genes with known roles in HF, including Drosha , Akap5 and Dicer1 . Several novel regulators were also identified, including the Serine Proteinase Inhibitor, Serpina3n , which resides in a locus that regulates the change in expression of 9.7% (1276 of 13156) of all genes and is strongly correlated with changes in heart weight after ISO treatment. In subsequent in vitro work, Serpina3n knockdown resulted in reduced cellular hypertrophy, changes to hypertrophy-related gene expression, and modulation of the expression of several genes linked to its locus. Conclusion: GWAS performed on over 20,000 transcripts in control and ISO-treated hearts identified 10 genomic loci that regulate over 5% of the expressed genes in the heart. Serpina3n is a novel master regulator of HF. Further analysis of other master regulatory loci will reveal additional genes and improve our understanding of the transcriptional networks that direct the progression towards heart failure.