title: Chromatin remodeling pathways in smooth muscle cell differentiation, and evidence for an integral role for p300.
abstract: BACKGROUND
  Phenotypic alteration of vascular smooth muscle cells (SMC) in response to injury or inflammation is an essential component of vascular disease. Evidence suggests that this process is dependent on epigenetic regulatory processes. P300, a histone acetyltransferase (HAT), activates crucial muscle-specific promoters in terminal (non-SMC) myocyte differentiation, and may be essential to SMC modulation as well.
  
  
  RESULTS
  We performed a subanalysis examining transcriptional time-course microarray data obtained using the A404 model of SMC differentiation. Numerous chromatin remodeling genes (up to 62% of such genes on our array platform) showed significant regulation during differentiation. Members of several chromatin-remodeling families demonstrated involvement, including factors instrumental in histone modification, chromatin assembly-disassembly and DNA silencing, suggesting complex, multi-level systemic epigenetic regulation. Further, trichostatin A, a histone deacetylase inhibitor, accelerated expression of SMC differentiation markers in this model. Ontology analysis indicated a high degree of p300 involvement in SMC differentiation, with 60.7% of the known p300 interactome showing significant expression changes. Knockdown of p300 expression accelerated SMC differentiation in A404 cells and human SMCs, while inhibition of p300 HAT activity blunted SMC differentiation. The results suggest a central but complex role for p300 in SMC phenotypic modulation.
  
  
  CONCLUSIONS
  Our results support the hypothesis that chromatin remodeling is important for SMC phenotypic switching, and detail wide-ranging involvement of several epigenetic modification families. Additionally, the transcriptional coactivator p300 may be partially degraded during SMC differentiation, leaving an activated subpopulation with increased HAT activity and SMC differentiation-gene specificity.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America. jspin@cvmed.stanford.edu
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.forename: Philip S
authors.initials: PS
authors.lastname: Tsao
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000235:genetics* / Q000378:metabolism*; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D020411:Oligonucleotide Array Sequence Analysis; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C494361:Ep300 protein, mouse