title: Cardiac expression of ms1/STARS, a novel gene involved in cardiac development and disease, is regulated by GATA4.
abstract: Ms1/STARS is a novel muscle-specific actin-binding protein that specifically modulates the myocardin-related transcription factor (MRTF)-serum response factor (SRF) regulatory axis within striated muscle. This ms1/STARS-dependent regulatory axis is of central importance within the cardiac gene regulatory network and has been implicated in cardiac development and postnatal cardiac function/homeostasis. The dysregulation of ms1/STARS is associated with and causative of pathological cardiac phenotypes, including cardiac hypertrophy and cardiomyopathy. In order to gain an understanding of the mechanisms governing ms1/STARS expression in the heart, we have coupled a comparative genomic in silico analysis with reporter, gain-of-function, and loss-of-function approaches. Through this integrated analysis, we have identified three evolutionarily conserved regions (ECRs), α, SINA, and DINA, that act as cis-regulatory modules and confer differential cardiac cell-specific activity. Two of these ECRs, α and DINA, displayed distinct regulatory sensitivity to the core cardiac transcription factor GATA4. Overall, our results demonstrate that within embryonic, neonatal, and adult hearts, GATA4 represses ms1/STARS expression with the pathologically associated depletion of GATA4 (type 1/type 2 diabetic models), resulting in ms1/STARS upregulation. This GATA4-dependent repression of ms1/STARS expression has major implications for MRTF-SRF signaling in the context of cardiac development and disease.
authors.affiliation: Cardiology Group, Department of Cardiovascular Sciences, Glenfield Hospital, University of Leicester, Leicester, United Kingdom. nc69@le.ac.uk
authors.forename: Samir
authors.initials: S
authors.lastname: Ounzain
authors.forename: Satoru
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Richard E
authors.initials: RE
authors.lastname: Peterson
authors.forename: Aibin
authors.initials: A
authors.lastname: He
authors.forename: Anna
authors.initials: A
authors.lastname: Motterle
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Donald R
authors.initials: DR
authors.lastname: Menick
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
authors.forename: Qiangrong
authors.initials: Q
authors.lastname: Liang
authors.forename: Nelson W
authors.initials: NW
authors.lastname: Chong
mesh_terms: D000818:Animals; D002460:Cell Line; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D006321:Heart / Q000196:embryology*; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
chemical_list: C518897:Abra protein, mouse; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D008840:Microfilament Proteins; C511173:Mrtfa protein, mouse; D026362:Serum Response Factor; D015534:Trans-Activators