Articles and Press Releases
July 14, 2016 Research Article
Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA
Summary: BRD4 governs pathological cardiac gene expression by binding acetylated chromatin, resulting in enhanced RNA polymerase II (Pol II) phosphorylation and transcription elongation. Here, we describe a signal-dependent mechanism for the regulation of BRD4 in cardiomyocytes. BRD4 expression is suppressed by microRNA-9 (miR-9), which targets the 3′ UTR of the Brd4 transcript. In response to stress stimuli, miR-9 is downregulated, leading to derepression of BRD4 and enrichment of BRD4 at long-range super-enhancers (SEs) associated with pathological cardiac genes. A miR-9 mimic represses stimulus-dependent targeting of BRD4 to SEs and blunts Pol II phosphorylation at proximal transcription start sites, without affecting BRD4 binding to SEs that control constitutively expressed cardiac genes. These findings suggest that dynamic enrichment of BRD4 at SEs genome-wide serves a crucial role in the control of stress-induced cardiac gene expression and define a miR-dependent signaling mechanism for the regulation of chromatin state and Pol II phosphorylation.
May 26, 2016 Review Article
Sarcomeres and Cardiac Growth: Tension in the Relationship
Abstract: Genetic mutations in the cardiomyocyte contractile apparatus cause aberrant cardiac growth categorized morphologically as hypertrophic or dilated. A recent study leverages an array of mutant mouse models to extrapolate a new integrated parameter: the myofilament 'tension index', which predicts patterns of cardiac growth resulting from individual sarcomeric mutations. These findings may inform genotype-specific therapies.
December 8, 2015 Research Article
Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program
Abstract: Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC–KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.
November 23, 2015 Press Release
Gene Identified that Produces the Benefits of Steroids, but Without the Detrimental Side Effects
Scientists have revealed that glucocorticoids, a class of steroid hormones that are commonly prescribed as drugs, enhance muscle endurance and alleviate muscular dystrophy through activation of the gene KLF15. Critically, this pathway is not involved in muscle wasting or the other major detrimental effects of prolonged steroid use. The discovery, published in The Proceedings of the National Academy of Sciences, could lead to the development of new medications that improve muscle function without the negative consequences caused by long-term steroid exposure. This advance is especially important for progressive muscle wasting diseases like Duchenne’s muscular dystrophy (DMD).
August 7, 2013 News
Researchers discover new designer compound that treats heart failure
Researchers from Case Western Reserve University School of Medicine and the Dana-Farber Cancer Institute have made a fundamental discovery relevant to the understanding and treatment of heart failure, a leading cause of death worldwide. The team discovered a new molecular pathway responsible for causing heart failure and showed that a first-in-class prototype drug, JQ1, blocks this pathway to protect the heart from damage.
August 5, 2013 News
Cleveland Cardiologist Discovers Possible New Heart Failure Therapy
A new study released in the peer-reviewed journal Cell highlights a discovery that could change the way heart failure is treated. The work was done by a young cardiologist who saw patients returning too many times to the intensive care unit at University Hospitals. Ideastream's Sarah Jane Tribble explains the research and its possible impact.
August 1, 2013 Press Release
New Target in Heart Failure
Researchers from Harvard Medical School, Dana-Farber Cancer Institute and Case Western Reserve University School of Medicine have made a fundamental discovery relevant to the understanding and treatment of heart failure, a leading cause of death worldwide. The team discovered a new molecular pathway responsible for causing heart failure and showed that a first-in-class prototype drug, JQ1, blocks this pathway to protect the heart from damage.