Skip to main content
Article thumbnail
Location of Repository

Regulatory characterisation of the novel gene, myocyte stress 1

By Samir Ounzain

Abstract

Myocyte stress 1 (ms1) is a striated muscle actin binding protein required for muscle\ud specific activity of the myocardin related transcription factor (MRTF)/serum response\ud factor (SRF) transcriptional pathway. Previous work in our group demostrated that\ud cardiac ms1 is transiently up-regulated after pressure overload suggesting a possible role in the initial signalling of the hypertrophic response. Subsequent studies have supported this and demonstrated that ms1 plays an important role in cardiac development and physiology. To date, little is known about the molecular mechanisms that govern striated muscle specific expression of ms1. In order to delineate ms1 regulation and function, a strategy of comparative in silico analysis coupled with experimental characterisation was used. In silico analysis identified four genomic intervals of potential regulatory function designated PP, UP1, UP2 and UP3. Using in vitro and in vivo appraoches, important cardiac regulatory roles for these domains were defined. The PP domain represents the basal promoter and is required for all regulatory contexts. This domain serves to intergrate context specific regulatory signals from the distal UP2 and UP3 domains. Within the heart the cardiac transcription factor GATA4, and the calcineurin singalling pathway confer cardiac regulatory function on the PP, UP2 and UP3 domains. Within skeletal muscle, MyoD binding sites within the PP and UP1 domain were identified, which mediate temporal induction of ms1 during myogenesis. Both cardiac and skeletal regulatory processes were dependent on epigenetic phenomena with histone acetylation being a major determinant for ms1 expression. Collectively, these findings demonstrate that ms1 transcriptional regulation is mediated by the complex interplay of context specific regulatory domains and binding factors. Therefore through ms1, important striated muscle gene regulatory networks (GRNs) (GATA4, Mef2 and MyoD GRNs) can integrate with SRF, thus exquisitely controlling biological processes in muscle. It is proposed that dysregulation of ms1 expression may result in pathological\ud phenotypes. Therefore, the insights obtained here may allow for the therapeutic manipulation of ms1 expression in pathological settings and potentially lead to effective paliatation of such phenotypes

Publisher: University of Leicester
Year: 2008
OAI identifier: oai:lra.le.ac.uk:2381/8208

Suggested articles

Citations

  1. (2005). (2002b) Impaired cardiac hypertrophic response in Calcineurin Abeta -deficient mice. Proc Natl Acad Sci
  2. (2005). Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes.
  3. (1999). Acetylation of MyoD directed by PCAF is necessary for the execution of the muscle program. doi
  4. (2003). Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice. doi
  5. (2002). Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice.
  6. (1996). Avian serum response factor expression restricted primarily to muscle cell lineages is required for alpha-actin gene transcription. doi
  7. (1999). Cooperative interaction between GATA-4 and GATA-6 regulates myocardial gene expression. doi
  8. (2002). Distinct roles of mitogen-activated protein kinase pathways in GATA-4 transcription factor-mediated regulation of B-type natriuretic peptide gene. doi
  9. (2005). Focal adhesion kinase mediates MEF2 and c-Jun activation by stretch: role in the activation of the cardiac hypertrophic genetic program. doi
  10. (2005). Genome-wide screening for target regions of histone deacetylases in cardiomyocytes.
  11. (2003). Histone and chromatin cross-talk. doi
  12. (1977). Identification of regulatory elements mediating cardiac-specific expression and upregulation.
  13. (2003). Interaction with GATA transcription factors provides a mechanism for cell-specific effects of c-Fos. doi
  14. (2000). Left ventricular hypertrophy: pathogenesis, detection, and prognosis. doi
  15. (1999). MEF2 is upregulated during cardiac hypertrophy and is required for normal post-natal growth of the myocardium. doi
  16. (1997). Modular regulation of muscle gene transcription: a mechanism for muscle cell diversity. doi
  17. (2004). Molecular regulation of vascular smooth muscle cell differentiation in development and disease. doi
  18. (1993). MyoD and myogenin act on the chicken myosin light-chain 1 gene as distinct transcriptional factors. doi
  19. (2004). Target gene-specific modulation of myocardin activity by GATA transcription factors. Mol Cell Biol 24(19): 8519-8528 Ohkawa Y, Marfella CG, Imbalzano AN (2006) Skeletal muscle specification by myogenin and Mef2D via the SWI/SNF ATPase Brg1.
  20. (2003). Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. doi
  21. (2000). The genome sequence of Drosophila melanogaster.
  22. (1996). The role of protein kinases in adaptational growth of the heart. doi
  23. (2003). Therapeutic strategies for patients hospitalized with worsening heart failure. doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.