Abstract 17037: CTCF Regulates Fetal Genes and is Inversely Correlated with Cardiac Muscle Size Across 100 Mouse Strains
Heart failure is accompanied by abnormal gene expression, however the global chromatin structural mechanisms responsible for transcriptional changes are unknown. We hypothesized that specific chromatin structural proteins orchestrate gene expression in the normal and diseased myocyte. The conserved zinc finger protein CTCF has been shown in diseases such as cancer to regulate transcription, enhancer function, and maintenance of 3D chromatin structure. The objective of this study was to investigate the role of CTCF in cardiac growth and pathology.
We conducted an unbiased systems genomics analysis-in which ~100 strains of mice were treated with isoproterenol (3 wk) followed by transcriptome and phenotype analyse-to investigate the genetic architecture of heart failure. This analysis revealed a strong negative correlation between CTCF mRNA expression and cardiac hypertrophy as measured by heart weight (r2=0.076, p=9.7E-9), left ventricular mass (r2=0.053, p=9.8E-8) and left ventricular internal diameter in diastole (r2=0.033, p=1.6E-5; association with ejection fraction was not significant, r2=0.007, p=0.63). We observed an 80% down-regulation of CTCF at the mRNA level, and 60% at the protein level, in neonatal rat ventricular myocytes (NRVMs) 48h following treatment with either isoproterenol (1umol) or phenylephrine (10umol). RT-PCR in agonist-treated NRVMs confirmed activation of the fetal gene program. However, siRNA mediated CTCF knockdown resulted in the opposite scenario, wherein SERCA and alpha-MHC were up-regulated while ANF and beta-MHC were down-regulated. The effect of CTCF KD on fetal gene expression is still observed when cells are simultaneously treated with hypertrophic agonists, suggesting that loss of CTCF partially prevents activation of these genes following acute hypertrophic stress. Lastly, CTCF KD induced cell death in NRVMs, implying that CTCF is an essential protein for myocyte survival. These data indicate that CTCF is involved in preservation of normal gene expression patterns in the healthy heart and its levels are genetically correlated with cardiac muscle size.
Author Disclosures: M. Rosa-Garrido: None. C. Rau: None. E. Soehalim: None. J. Wang: None. A.J. Lusis: None. Y. Wang: None. T.M. Vondriska: None.
- © 2014 by American Heart Association, Inc.