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      BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure.

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          Abstract

          Despite current standard of care, the average 5-year mortality after an initial diagnosis of heart failure (HF) is about 40%, reflecting an urgent need for new therapeutic approaches. Previous studies demonstrated that the epigenetic reader protein bromodomain-containing protein 4 (BRD4), an emerging therapeutic target in cancer, functions as a critical coactivator of pathologic gene transactivation during cardiomyocyte hypertrophy. However, the therapeutic relevance of these findings to human disease remained unknown. We demonstrate that treatment with the BET bromodomain inhibitor JQ1 has therapeutic effects during severe, preestablished HF from prolonged pressure overload, as well as after a massive anterior myocardial infarction in mice. Furthermore, JQ1 potently blocks agonist-induced hypertrophy in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Integrated transcriptomic analyses across animal models and human iPSC-CMs reveal that BET inhibition preferentially blocks transactivation of a common pathologic gene regulatory program that is robustly enriched for NFκB and TGF-β signaling networks, typified by innate inflammatory and profibrotic myocardial genes. As predicted by these specific transcriptional mechanisms, we found that JQ1 does not suppress physiological cardiac hypertrophy in a mouse swimming model. These findings establish that pharmacologically targeting innate inflammatory and profibrotic myocardial signaling networks at the level of chromatin is effective in animal models and human cardiomyocytes, providing the critical rationale for further development of BET inhibitors and other epigenomic medicines for HF.

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          Most cited references 41

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          Is Open Access

          featureCounts: An efficient general-purpose program for assigning sequence reads to genomic features

           ,  ,   (2013)
          Next-generation sequencing technologies generate millions of short sequence reads, which are usually aligned to a reference genome. In many applications, the key information required for downstream analysis is the number of reads mapping to each genomic feature, for example to each exon or each gene. The process of counting reads is called read summarization. Read summarization is required for a great variety of genomic analyses but has so far received relatively little attention in the literature. We present featureCounts, a read summarization program suitable for counting reads generated from either RNA or genomic DNA sequencing experiments. featureCounts implements highly efficient chromosome hashing and feature blocking techniques. It is considerably faster than existing methods (by an order of magnitude for gene-level summarization) and requires far less computer memory. It works with either single or paired-end reads and provides a wide range of options appropriate for different sequencing applications. featureCounts is available under GNU General Public License as part of the Subread (http://subread.sourceforge.net) or Rsubread (http://www.bioconductor.org) software packages.
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            Cardiac Fibrosis: The Fibroblast Awakens.

            Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis.
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              Cardiac plasticity.

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                Author and article information

                Journal
                Sci Transl Med
                Science translational medicine
                American Association for the Advancement of Science (AAAS)
                1946-6242
                1946-6234
                May 17 2017
                : 9
                : 390
                Affiliations
                [1 ] Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
                [2 ] Institute for Transformative Molecular Medicine and Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA.
                [3 ] BioInfo, Plantagenet, Ontario K0B 1L0, Canada.
                [4 ] Division of Cardiovascular Medicine, Department of Medicine, and Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
                [5 ] Division of Cardiology, Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA 94158, USA.
                [6 ] Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
                [7 ] Division of Cardiology, Department of Medicine, Consortium for Fibrosis Research & Translation, University of Colorado, Anschutz Medical Campus, Denver, CO 80204, USA.
                [8 ] Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. saptarsi.haldar@gladstone.ucsf.edu.
                [9 ] Division of Cardiology, Department of Medicine, and Cardiovascular Research Institute, University of California San Francisco School of Medicine, San Francisco, CA 94158, USA.
                Article
                9/390/eaah5084
                10.1126/scitranslmed.aah5084
                28515341

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