Rhonda Bassel-Duby

University of Texas Southwestern Medical Center, Dallas, TX, United States

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Publications (183)1870.05 Total impact

  • [Show abstract] [Hide abstract] ABSTRACT: Polypyrimidine Tract Binding Protein (PTB) regulates pre-mRNA splicing, having special relevance for determining gene expression in the differentiating muscle. We have previously shown that PTB protein abundance is progressively reduced during heart development without reduction of its own transcript. Simultaneous reduction of Histone Deacetylase (HDAC) expression prompted us to investigate the potential link between these events. HDAC5-deficient mice have reduced cardiac PTB protein abundance, and HDAC inhibition in myocytes causes a reduction in endogenous expression of cFLIP and caspase-dependent cleavage of PTB. In agreement with this, cardiac PTB expression is abnormally high in mice with cardiac-specific executioner caspase deficiency and cellular FLICE-like inhibitory protein (cFLIP) overexpression prevents PTB cleavage in vitro. Caspase-dependent cleavage triggers further fragmentation of PTB and these fragments accumulate in the presence of proteasome inhibitors. Experimental modification of the above processes in vivo and in vitro results in coherent changes in the alternative splicing of tropomyosin-1 (TPM1) and tropomyosin-2 (TPM2) and Myocyte Enhancer Factor-2 (Mef2) genes. Thus, we report a pathway connecting HDAC, cFLIP and caspases regulating the progressive disappearance of PTB, which enables the expression of the adult variants of proteins involved in regulation of contraction and transcription during cardiac muscle development.
    No preview · Article · Feb 2013 · Journal of Cell Science
  • No preview · Article · Jan 2013
  • Ning Liu · Rhonda Bassel-Duby
    No preview · Chapter · Dec 2012
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    [Show abstract] [Hide abstract] ABSTRACT: The epicardium encapsulates the heart and functions as a source of multipotent progenitor cells and paracrine factors essential for cardiac development and repair. Injury of the adult heart results in reactivation of a developmental gene program in the epicardium, but the transcriptional basis of epicardial gene expression has not been delineated. We established a mouse embryonic heart organ culture and gene expression system that facilitated the identification of epicardial enhancers activated during heart development and injury. Epicardial activation of these enhancers depends on a combinatorial transcriptional code centered on CCAAT/enhancer binding protein (C/EBP) transcription factors. Disruption of C/EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function. These findings reveal a transcriptional basis for epicardial activation and heart injury, providing a platform for enhancing cardiac regeneration.
    Full-text · Article · Dec 2012 · Science
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    [Show abstract] [Hide abstract] ABSTRACT: Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus, these miRNAs provide potential targets for pharmacologic intervention in obesity and metabolic syndrome.
    Full-text · Article · Sep 2012 · Proceedings of the National Academy of Sciences
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    [Show abstract] [Hide abstract] ABSTRACT: Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological HDAC inhibitors, primarily those targeted to class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed under-standing of the role of class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.
    Full-text · Article · Aug 2012 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    [Show abstract] [Hide abstract] ABSTRACT: The adult mammalian heart possesses little regenerative potential following injury. Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodelling and susceptibility to arrhythmias. Cardiac fibroblasts account for a majority of cells in the heart and represent a potential cellular source for restoration of cardiac function following injury through phenotypic reprogramming to a myocardial cell fate. Here we show that four transcription factors, GATA4, HAND2, MEF2C and TBX5, can cooperatively reprogram adult mouse tail-tip and cardiac fibroblasts into beating cardiac-like myocytes in vitro. Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodelling following myocardial infarction. Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules.
    Full-text · Article · May 2012 · Nature
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    [Show abstract] [Hide abstract] ABSTRACT: Skeletal muscle injury activates adult myogenic stem cells, known as satellite cells, to initiate proliferation and differentiation to regenerate new muscle fibers. The skeletal muscle-specific microRNA miR-206 is upregulated in satellite cells following muscle injury, but its role in muscle regeneration has not been defined. Here, we show that miR-206 promotes skeletal muscle regeneration in response to injury. Genetic deletion of miR-206 in mice substantially delayed regeneration induced by cardiotoxin injury. Furthermore, loss of miR-206 accelerated and exacerbated the dystrophic phenotype in a mouse model of Duchenne muscular dystrophy. We found that miR-206 acts to promote satellite cell differentiation and fusion into muscle fibers through suppressing a collection of negative regulators of myogenesis. Our findings reveal an essential role for miR-206 in satellite cell differentiation during skeletal muscle regeneration and indicate that miR-206 slows progression of Duchenne muscular dystrophy.
    Preview · Article · May 2012 · The Journal of clinical investigation
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    [Show abstract] [Hide abstract] ABSTRACT: Obesity, type 2 diabetes, and heart failure are associated with aberrant cardiac metabolism. We show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. Cardiac-specific overexpression of MED13 or pharmacologic inhibition of miR-208a in mice confers resistance to high-fat diet-induced obesity and improves systemic insulin sensitivity and glucose tolerance. Conversely, genetic deletion of MED13 specifically in cardiomyocytes enhances obesity in response to high-fat diet and exacerbates metabolic syndrome. The metabolic actions of MED13 result from increased energy expenditure and regulation of numerous genes involved in energy balance in the heart. These findings reveal a role of the heart in systemic metabolic control and point to MED13 and miR-208a as potential therapeutic targets for metabolic disorders.
    Full-text · Article · Apr 2012 · Cell
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    Preview · Dataset · Apr 2012
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    [Show abstract] [Hide abstract] ABSTRACT: MEF2 (A–D) transcription factors govern development, differentiation and maintenance of various cell types including neurons. The role of MEF2 isoforms in the brain has been studied using in vitro manipulations with only MEF2C examined in vivo. In order to understand specific as well as redundant roles of the MEF2 isoforms, we generated brain-specific deletion of MEF2A and found that Mef2aKO mice show normal behavior in a range of paradigms including learning and memory. We next generated Mef2a and Mef2d brain-specific double KO (Mef2a/dDKO) mice and observed deficits in motor coordination and enhanced hippocampal short-term synaptic plasticity, however there were no alterations in learning and memory, Schaffer collateral pathway long-term potentiation, or the number of dendritic spines. Since previous work has established a critical role for MEF2C in hippocampal plasticity, we generated a Mef2a, Mef2c and Mef2d brain-specific triple KO (Mef2a/c/ dTKO). Mef2a/c/d TKO mice have early postnatal lethality with increased neuronal apoptosis, indicative of a redundant role for the MEF2 factors in neuronal survival. We examined synaptic plasticity in the intact neurons in the Mef2a/c/d TKO mice and found significant impairments in short-term synaptic plasticity suggesting that MEF2C is the major isoform involved in hippocampal synaptic function. Collectively, these data highlight the key in vivo role of MEF2C isoform in the brain and suggest that MEF2A and MEF2D have only subtle roles in regulating hippocampal synaptic function.
    Full-text · Article · Apr 2012 · PLoS ONE
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    [Show abstract] [Hide abstract] ABSTRACT: Early reperfusion of ischemic cardiac tissue remains the most effective intervention for improving clinical outcome following myocardial infarction. However, abnormal increases in intracellular Ca²⁺ during myocardial reperfusion can cause cardiomyocyte death and consequent loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Therapeutic modulation of Ca²⁺ handling provides some cardioprotection against the paradoxical effects of restoring blood flow to the heart, highlighting the significance of Ca²⁺ overload to IR injury. Cardiac IR is also accompanied by dynamic changes in the expression of microRNAs (miRNAs); for example, miR-214 is upregulated during ischemic injury and heart failure, but its potential role in these processes is unknown. Here, we show that genetic deletion of miR-214 in mice causes loss of cardiac contractility, increased apoptosis, and excessive fibrosis in response to IR injury. The cardioprotective roles of miR-214 during IR injury were attributed to repression of the mRNA encoding sodium/calcium exchanger 1 (Ncx1), a key regulator of Ca²⁺ influx; and to repression of several downstream effectors of Ca²⁺ signaling that mediate cell death. These findings reveal a pivotal role for miR-214 as a regulator of cardiomyocyte Ca²⁺ homeostasis and survival during cardiac injury.
    Full-text · Article · Mar 2012 · The Journal of clinical investigation
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    [Show abstract] [Hide abstract] ABSTRACT: Maintenance of skeletal muscle structure and function requires efficient and precise metabolic control. Autophagy plays a key role in metabolic homeostasis of diverse tissues by recycling cellular constituents, particularly under conditions of caloric restriction, thereby normalizing cellular metabolism. Here we show that histone deacetylases (HDACs) 1 and 2 control skeletal muscle homeostasis and autophagy flux in mice. Skeletal muscle-specific deletion of both HDAC1 and HDAC2 results in perinatal lethality of a subset of mice, accompanied by mitochondrial abnormalities and sarcomere degeneration. Mutant mice that survive the first day of life develop a progressive myopathy characterized by muscle degeneration and regeneration, and abnormal metabolism resulting from a blockade to autophagy. HDAC1 and HDAC2 regulate skeletal muscle autophagy by mediating the induction of autophagic gene expression and the formation of autophagosomes, such that myofibers of mice lacking these HDACs accumulate toxic autophagic intermediates. Strikingly, feeding HDAC1/2 mutant mice a high-fat diet from the weaning age releases the block in autophagy and prevents myopathy in adult mice. These findings reveal an unprecedented and essential role for HDAC1 and HDAC2 in maintenance of skeletal muscle structure and function and show that, at least in some pathological conditions, myopathy may be mitigated by dietary modifications.
    Full-text · Article · Jan 2012 · Proceedings of the National Academy of Sciences
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    [Show abstract] [Hide abstract] ABSTRACT: Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.
    Full-text · Article · Jan 2012 · Nature
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    Dataset: Figure S4
    [Show abstract] [Hide abstract] ABSTRACT: MiR-181 interaction sites within murine LIF. A) Predicted interactions of miR-181a and miR-181d with their binding sites in the murine LIF 3′UTR. RNAhybrid algorithm and the microRNA resource (www.microrna.org) were used to assess potential miR binding target sites. B) List of primers used for PCR amplification of miR-181a, miR-181d, and the Lif 3′ UTR. C) Mutation of the Lif sequences at site 1 and site 572 are shown. The seed sequence of miR-181 is underlined. (TIF)
    Full-text · Dataset · Nov 2011
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    [Show abstract] [Hide abstract] ABSTRACT: Background Physiological stress evokes rapid changes in both the innate and adaptive immune response. Immature αβ T cells developing in the thymus are particularly sensitive to stress, with infections and/or exposure to lipopolysaccharide or glucocorticoids eliciting a rapid apoptotic program. MicroRNAs are a class of small, non-coding RNAs that regulate global gene expression by targeting diverse mRNAs for degradation. We hypothesized that a subset of thymically encoded microRNAs would be stress responsive and modulate thymopoiesis. We performed microRNA profiling of thymic microRNAs isolated from control or stressed thymic tissue obtained from mice. We identified 18 microRNAs that are dysregulated >1.5-fold in response to lipopolysaccharide or the synthetic corticosteroid dexamethasone. These included the miR-17-90 cluster, which have anti-apoptotic functions, and the miR-181 family, which contribute to T cell tolerance. The stress-induced changes in the thymic microRNAs are dynamically and distinctly regulated in the CD4−CD8−, CD4+CD8+, CD4+CD8−, and CD4−CD8+ thymocyte subsets. Several of the differentially regulated murine thymic miRs are also stress responsive in the heart, kidney, liver, brain, and/or spleen. The most dramatic thymic microRNA down modulated is miR-181d, exhibiting a 15-fold reduction following stress. This miR has both similar and distinct gene targets as miR-181a, another member of miR-181 family. Many of the differentially regulated microRNAs have known functions in thymopoiesis, indicating that their dysregulation will alter T cell repertoire selection and the formation of naïve T cells. This data has implications for clinical treatments involving anti-inflammatory steroids, ablation therapies, and provides mechanistic insights into the consequences of infections.
    Full-text · Article · Nov 2011 · PLoS ONE
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    Dataset: Figure S2
    [Show abstract] [Hide abstract] ABSTRACT: MiR expression patterns in different tissues. A) Differential expression of microRNAs in the thymic tissue. RNA was prepared from the thymus of age- and sex- matched control and CD3ε−/− C57BL/6 mice. The samples were used to probe a murine microRNA array containing 649 miRs (LC Sciences). Data represent differential expression levels of selected miRs from two independent sample preparations. B) Differential expression of stress responsive miRs in diverse tissues. Male mice were injected with PBS, LPS or Dex. Total RNA was isolated from the heart, kidney, and liver of control (PBS) and LPS- or Dex- treated mice at 72 h post-injection. The individual miRs (miR-150, miR-205, miR-128, miR-181a, miR-181b, miR-181d) were detected by Northern blotting. The relative amounts of a control RNA were determined by blotting for U6. C) Male mice were injected with PBS, LPS or Dex. Total RNA was isolated from the heart, kidney, liver, brain, spleen, and thymus of control (PBS) and LPS- or Dex- treated mice at 72 h post-injection. The individual miRs (miR-15a, miR-17, miR-20a, miR-20b, miR-26b, miR-106a, miR-125-5p, miR-342-3p) were detected by Northern blotting. The relative amounts of a control RNA were determined by blotting for U6. (TIF)
    Full-text · Dataset · Nov 2011
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    Dataset: Figure S1
    [Show abstract] [Hide abstract] ABSTRACT: Lipopolysaccharide and dexamethasone have differential effects on peripheral lymphocytes. A) Lymphocytes were isolated from control (PBS injected, t = 72 h), LPS, or Dex injected mice (t = 24, 48 and 72 h). The total lymphoid cellularity was determined. B–D) The splenic cells were stained with fluorochrome-labeled anti-B220, anti-CD3, anti-CD4, and anti-CD8 mAbs and analyzed by flow cytometry. The absolute number of B) B220+ B cells, C) CD4+CD8− T cells, and D) CD4−CD8+ T cells were calculated at 24, 48, and 72 h post-injection, after appropriate electronic gating to determine the percentage of each population. Data are representative of mean +/− SD from at least 5 mice per group (*p<0.05, **p<0.01, *** p<0.001 versus PBS control; one-way ANOVA analyses. E) Representative heat map shows differential expression of miRNAs in the thymus of control (PBS) and LPS-treated mice (t = 72 h). The samples were labeled with Cy3 and Cy5, respectively, and used to probe a murine microRNA array containing 649 miRs (LC Sciences). Red indicates high miR expression; green indicates low miR expression in thymic tissue. Data are shown for one of three separate microarray analyses with control and LPS injected mice. (TIF)
    Full-text · Dataset · Nov 2011
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    Dataset: Data Set S1
    [Show abstract] [Hide abstract] ABSTRACT: Standard Data Analysis Report. (PDF)
    Full-text · Dataset · Nov 2011
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    Dataset: Figure S5
    [Show abstract] [Hide abstract] ABSTRACT: Dose-response analysis of miR-181 target genes. A beta-galactosidase expressing vector and the luciferase reporter constructs containing the 3′untranslated region of murine Cd69, Prox1, and Lif genes were co-transfected along with vector alone or vectors expressing miR-181a or miR-181d at the indicated amounts (100 or 300 ng). Firefly luciferase was normalized to beta-galactosidase activity. Each graph represents mean +/− SD, using the ratio of the normalized luciferase activity in miR-181 and control vector transfections. This was done in three independent experiments, with each sample tested in triplicate or quadruplicate (n.s., not significant, * p<0.05, ** p<0.01, *** p<0.001 versus vector control, unpaired Student's t-test). (TIF)
    Full-text · Dataset · Nov 2011

Publication Stats

17k Citations
1,870.05 Total Impact Points

Institutions

  • 1993-2010
    • University of Texas Southwestern Medical Center
      • • Department of Molecular Biology
      • • Division of General Internal Medicine
      • • Department of Internal Medicine
      Dallas, TX, United States
  • 1996-2008
    • University of Texas at Dallas
      • Molecular Biology
      Richardson, Texas, United States
  • 2004
    • Koninklijke Nederlandse Akademie van Wetenschappen
      Amsterdamo, North Holland, Netherlands
  • 2002
    • Duke University Medical Center
      Durham, North Carolina, United States
    • Duke University
      Durham, North Carolina, United States
  • 1986-2002
    • Harvard Medical School
      • Department of Cell Biology
      Boston, Massachusetts, United States
    • Massachusetts General Hospital
      • Department of Neurology
      Boston, Massachusetts, United States
  • 1985
    • McGill University
      • Department of Biochemistry
      Montréal, Quebec, Canada