RNA-Seq identifies novel myocardial gene expression signatures of heart failure

Liu, Yichuan; Morley, Michael; Brandimarto, Jeffrey; Hannenhalli, Sridhar; Hu, Yu; Ashley, Euan A.; Tang, W.H. Wilson; Moravec, Christine S.; Margulies, Kenneth B.; Cappola, Thomas P.; Li, Mingyao

doi:10.1016/j.ygeno.2014.12.002

Cited by 242 publications

(219 citation statements)

References 29 publications

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“…1C). In line with our findings, a recent RNA-sequencing study of samples from failing human hearts reported increased PDE1C expression in both ischemic heart disease and dilated cardiomyopathy (15).…”

Section: Pde1c Expression In Failing Heartssupporting

confidence: 92%

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

Knight

Chen

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β-stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.cyclic nucleotide | phosphodiesterase | cardiac remodeling | heart failure

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Section: Pde1c Expression In Failing Heartssupporting

confidence: 92%

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

Knight

Chen

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Three (influenza infection, bacterial sepsis and pulmonary tuberculosis) were used as previously described (18–21), and three new analyses were constructed according to criteria below (cardiomyopathy (44–55), kidney transplant rejection (14,56–67) and lung adenocarcinoma (68–81), Supplementary Tables S1–S3). The three new analyses were arrived at by repeatedly performing systematic searches of NIH GEO and ArrayExpress for clinical ( in vivo ) studies that (i) yielded an aggregate sample size of >1000 samples from >10 datasets, (ii) measured the same disease state and had the same type of controls in each dataset and (iii) had appropriate study design (excluding studies where, for instance, healthy controls came from one batch and diseased samples were processed separately).…”

Section: Methodsmentioning

confidence: 99%

Methods to increase reproducibility in differential gene expression via meta-analysis

et al. 2016

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Findings from clinical and biological studies are often not reproducible when tested in independent cohorts. Due to the testing of a large number of hypotheses and relatively small sample sizes, results from whole-genome expression studies in particular are often not reproducible. Compared to single-study analysis, gene expression meta-analysis can improve reproducibility by integrating data from multiple studies. However, there are multiple choices in designing and carrying out a meta-analysis. Yet, clear guidelines on best practices are scarce. Here, we hypothesized that studying subsets of very large meta-analyses would allow for systematic identification of best practices to improve reproducibility. We therefore constructed three very large gene expression meta-analyses from clinical samples, and then examined meta-analyses of subsets of the datasets (all combinations of datasets with up to N/2 samples and K/2 datasets) compared to a ‘silver standard’ of differentially expressed genes found in the entire cohort. We tested three random-effects meta-analysis models using this procedure. We showed relatively greater reproducibility with more-stringent effect size thresholds with relaxed significance thresholds; relatively lower reproducibility when imposing extraneous constraints on residual heterogeneity; and an underestimation of actual false positive rate by Benjamini–Hochberg correction. In addition, multivariate regression showed that the accuracy of a meta-analysis increased significantly with more included datasets even when controlling for sample size.

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“…Comparison of RCM versus NDR (controls) yielded 760 differentially expressed genes with at least a 1.5 fold difference and moderated t-test p < 0.05. To further control for possible differences in age or cardiac sample site, we analyzed previously described datasets profiling non-diseased human left and right ventricles (GSE57338 and GSE36761; See Table 3 for description of all datasets)910. We identified only a small number of genes anti-correlated with age (n = 10), none of which were increased in RCM (GSE57338).…”

Section: Resultsmentioning

confidence: 99%

Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics

Rindler

Hinton

Salomonis

et al. 2017

Sci Rep

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Pediatric restrictive cardiomyopathy (RCM) is a genetically heterogeneous heart disease with limited therapeutic options. RCM cases are largely idiopathic; however, even within families with a known genetic cause for cardiomyopathy, there is striking variability in disease severity. Although accumulating evidence implicates both gene expression and alternative splicing in development of dilated cardiomyopathy (DCM), there have been no detailed molecular characterizations of underlying pathways dysregulated in RCM. RNA-Seq on a cohort of pediatric RCM patients compared to other forms of adult cardiomyopathy and controls identified transcriptional differences highly common to the cardiomyopathies, as well as those unique to RCM. Transcripts selectively induced in RCM include many known and novel G-protein coupled receptors linked to calcium handling and contractile regulation. In-depth comparisons of alternative splicing revealed splicing events shared among cardiomyopathy subtypes, as well as those linked solely to RCM. Genes identified with altered alternative splicing implicate RBM20, a DCM splicing factor, as a potential mediator of alternative splicing in RCM. We present the first comprehensive report on molecular pathways dysregulated in pediatric RCM including unique/shared pathways identified compared to other cardiomyopathy subtypes and demonstrate that disruption of alternative splicing patterns in pediatric RCM occurs in the inverse direction as DCM.

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RNA-Seq identifies novel myocardial gene expression signatures of heart failure

Cited by 242 publications

References 29 publications

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

Methods to increase reproducibility in differential gene expression via meta-analysis

Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics

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