Mechanisms in transcriptional regulation during cardiac hypertrophy

Summary

Principal Investigator: Maha Abdellatif
Abstract: DESCRIPTION (provided by applicant): Cardiac hypertrophy is characterized by a generalized increase in gene expression that is commensurate with the increase in myocyte size and mass, on which is superimposed more robust changes in the expression of specialized genes. While transcriptional regulation of some of those genes has been validated, we do not have comprehensive, genome-wide, knowledge of which genes are regulated by transcription vs. those that may be independently regulated by posttranscriptional mechanisms involving microRNA. Additionally, we do not know the mode of transcriptional regulation - de novo RNA polymerase II (pol II) recruitment vs. the release of paused pol II - or the regulators involved. One of the earliest changes observed after applying pressure overload on a mouse heart, is the downregulation of miR-1, which precedes any other miRNA changes, the increase in cardiac mass, or contractile dysfunction. This suggested that miR-1 might be a cause rather than an effect of the underlying pathogenesis. Our preliminary data show that miR-1 targets two major components of basic transcription, general transcription factor 2B (TFIIB) and cyclin-dependent kinase 9 (Cdk9), which are the key regulators of pol II recruitment and elongation, respectively. Inhibiting miR-1 with locked nucleic acid- modified anti-miR oligo in the heart is sufficient for inducing upregulation of these targets, and conversely overexpression of miR-1 suppresses their expression. More significantly, chromatin immunoprecipitation-deep sequencing analysis (ChIP-Seq) reveals that supplementing cardiac myocytes with miR-1 suppresses de novo pol II recruitment on a subset of genes, while inducing pausing on another, in concordance with its suppression of TFIIB and Cdk9, respectively. The same subsets of genes are inversely regulated during cardiac hypertrophy as miR-1 is downregulated. In general, the regulation by de novo pol II recruitment and that by the release of promoter-paused pol II seem to be mutually exclusive. The former mainly regulates ~6% of genes mainly including those with specialized functions (e.g. contractile, extracellular matrix, immune response...etc), while the latter involve ~ 25% of expressed genes mainly including housekeeping/essential genes (e.g. protein and mRNA turnover genes, basal transcription factor, splicing genes...etc). These results led to the hypotheses for this grant. i- Downregulation of miR-1 is required for upregulation of TFIIB and Cdk9 during cardiac hypertrophy and, accordingly, the associated changes in gene expression. ii- Selective inhibition of TFIIB in the heart during cardiac hypertrophy will inhibit de novo recruitment of pol II to the promoters of a subset of genes (~6%) including those involved in the development of cardiomyopathy (e.g. ANF, BNP, alpha skeletal actin, collagen, etc.) This will not inhibit the increase in cardiac mass but will ameliorate contractile dysfunction during hypertrophy. iii- Selective inhibition of Cdk9 in the heart during cardiac hypertrophy will inhibit promoter clearance of paused pol II on all essential/housekeeping genes (~25%) in the heart (e.g. Vdac1, pinin, TFIIB, Cdk9, MAPK1, etc). This will inhibit the increase in cardiac mass and result in precipitous cardiac failure. The specific aims are 1) Identify the mechanisms involved in the regulation of TFIIB and Cdk9, and basic gene transcription, during cardiac hypertrophy. 2) Determine the role of TFIIB in gene transcription and the development of cardiac hypertrophy. 3) Determine the role of Cdk9 in gene transcription and the development of cardiac hypertrophy.
Funding Period: 2013-08-26 - 2017-05-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  2. Regulation of AT1R-signaling and pathology in vessels through microRNA
    Sadashiva S Karnik; Fiscal Year: 2013
    ..There is potential relevance for this knowledge base in understanding normal functioning aorta, vasculature in brain, kidney and heart, as well as the pathology of heart failure, atherosclerosis and aortic aneurysm. ..
  3. Genetic Analysis of microRNAs Function in Diabetic Cardiomyopathy
    Djamel Lebeche; Fiscal Year: 2013
    ..The elucidation of how cardiac miRNAs expression contributes to the development of diabetic cardiomyopathy will be important to interfere with disease-related pathways and may prove valuable as potential therapeutics. ..
  4. Biology and Novel Therapeutics of Cardiovascular Peptides
    John C Burnett; Fiscal Year: 2013
    ..Thus, this application brings together a highly collaborative team of physician-scientists with a highly translational proposal which should lead to innovative therapeutics for cardiorenal disease. ..
  5. The role of STIM1 in cardiac and skeletal muscle function
    Paul B Rosenberg; Fiscal Year: 2013
    ..abstract_text> ..
  6. Epigenetic Regulation of Cardiac Hypertrophy and Heart Failure
    Zhi Ping Liu; Fiscal Year: 2013
    ..The success of the proposal will provide mechanistic insights to design therapeutic strategies of utilizing this class of inhibitors to combat cardiac hypertrophy and failure in the future. ..
  7. Function and Regulation of CD-RAP
    Linda J Sandell; Fiscal Year: 2013
    ..As new transcription factors arise, specific mechanism of activity will be deciphered using our CD-RAP and COL2A1 gene models. ..
  8. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  9. Mechanisms of PMN and Endothelial-Mediated Lung Inflammation and Injury
    Asrar B Malik; Fiscal Year: 2013
    ..abstract_text> ..
  10. Endophenotypes of Sleep Apnea and Role of Obesity
    ALLAN IAN PACK; Fiscal Year: 2013
    ..It will lead to a new molecular signature of OSA that could transform the practice of medicine in this area in a new, cost-effective way. ..
  11. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  12. Pathobiology of Cardiac Dyssynchrony &Resynchronization
    DAVID ALAN KASS; Fiscal Year: 2013
    ..abstract_text> ..
  13. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
    ..abstract_text> ..
  14. Integrative genomics of human heart failure
    Wai Hong Wilson Tang; Fiscal Year: 2013
    ..Doing so will accelerate the translation of scientific knowledge to HF therapeutics. Moreover, all data and biosamples will be made available to the scientific community to promote a broad and durable impact on HF research. ..
  15. Dynamics of Cardiac Nuclei in Heart Disease
    Thomas M Vondriska; Fiscal Year: 2013
    ..This knowledge will provide a mechanistic basis for how the genome is reprogrammed with disease and help establish new paradigms for therapy. ..
  16. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  17. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
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  18. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
    ..abstract_text> ..
  19. The role of interleukin-18 in myocardial hypertrophy and failure
    Bysani Chandrasekar; Fiscal Year: 2013
    ..The primary goal of this proposal is to better understand the role of inflammatory cytokines, interleukin-18 in particular, in myocardial hypertrophy and its transition to failure. ..
  20. Regulation of myocardial growth and death by GSK-3
    Junichi Sadoshima; Fiscal Year: 2013
    ..The knowledge obtained from this investigation should be useful for the development of better treatment for heart failure, ischemic injury and stem cell therapy. ..
  21. Regulation and function of cGMP dependent protein kinase in cardiac hypertrophy
    Eiki Takimoto; Fiscal Year: 2013
    ..This project will clarify the underlying mechanisms for this beneficial impact from enhanced cGMP signaling pathway in the heart, focusing on a major downstream molecule and its interaction with other key regulators. ..
  22. Titin-based adaptations of cardiac function
    Henk L Granzier; Fiscal Year: 2013
    ....
  23. Role of Thrombospondin-4 in Cardiac Mechanotransduction
    Oscar Cingolani; Fiscal Year: 2013
    ..In addition both members of the mentoring committee serve as excellent role models for the applicant's career development into an independent investigator. ..
  24. Mechanism of SRF-N-mediated Cardiac Suppression
    Jiang Chang; Fiscal Year: 2013
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  25. Modulation of Ca Control of Cardiac Myofibrils
    R John Solaro; Fiscal Year: 2013
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  26. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..