title: Modifications of chromatin dynamics control Smad2 pathway activation in aneurysmal smooth muscle cells.
abstract: BACKGROUND
  The activation of the Smad2 signaling pathway is thought to play an important role in human aneurysmal diseases as described by an important body of research. We previously showed that constitutive Smad2 activation is associated with Smad2 mRNA overexpression in aneurysmal vascular smooth muscle cells (VSMCs), which is dependent on epigenetic regulation of the SMAD2 promoter involving histone modifications. However, the underlying molecular mechanisms controlling Smad2 overexpression are currently unknown.
  
  
  OBJECTIVE
  The aim of the present study is to understand the mechanisms regulating the constitutive Smad2 overexpression in VSMCs by identification of the histone-modifying enzymes, transcription factors, and cofactors responsible for Smad2 promoter activation in aneurysmal disease.
  
  
  RESULTS
  This study was performed on medial tissue extracts and primary cultures of VSMCs of human thoracic aneurysms (n=17) and normal thoracic aortas (n=10). Here, we demonstrate that the activation of SMAD2 promoter is driven by the recruitment of a multipartner complex, including the transcription factor p53 and histone acetyltransferases. Remarkably, the transcriptional regulatory network of the SMAD2 promoter is dramatically altered in human aneurysmal VSMCs in vitro and in situ with a switch from Myc-dependent repression of SMAD2 in normal vessel to a p53-dependent activation of SMAD2 in aneurysms. Furthermore, histone acetyltransferases p300 and P300/CBP-associated protein play a major role in SMAD2 promoter activation by acting on histone acetylation, p53 recruitment, and acetylation.
  
  
  CONCLUSIONS
  These results provide evidence for a major role of p53 and the complex composed of p300 and p300/CBP-associated protein in Smad2 activation in human aneurysmal VSMCs.
authors.affiliation: From the INSERM, U698, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Gomez
authors.forename: Ketty
authors.initials: K
authors.lastname: Kessler
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
authors.forename: Roger
authors.initials: R
authors.lastname: Vranckx
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001011:Aorta / Q000473:pathology; D001014:Aortic Aneurysm / Q000378:metabolism* / Q000473:pathology; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D005260:Female; D053263:Gene Regulatory Networks; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D002843:Chromatin; D012333:RNA, Messenger; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016159:Tumor Suppressor Protein p53; D051548:Histone Acetyltransferases; D050880:p300-CBP Transcription Factors
keywords: epigenetics; epigenomics; marfan syndrome; smooth muscle cells; tumor suppressor protein p53