title: Functional redundancy of SWI/SNF catalytic subunits in maintaining vascular endothelial cells in the adult heart.
abstract: BACKGROUND
  Mating type switching/sucrose non-fermenting (SWI/SNF) chromatin-remodeling complexes utilize either BRG1 or BRM as a catalytic subunit to alter nucleosome position and regulate gene expression. BRG1 is required for vascular endothelial cell (VEC) development and embryonic survival, whereas BRM is dispensable.
  
  
  OBJECTIVE
  To circumvent embryonic lethality and study Brg1 function in adult tissues, we used conditional gene targeting. To evaluate possible Brg1-Brm redundancy, we analyzed Brg1 mutant mice on wild-type and Brm-deficient backgrounds.
  
  
  RESULTS
  The inducible Mx1-Cre driver was used to mutate Brg1 in adult mice. These conditional-null mutants exhibited a tissue-specific phenotype and unanticipated functional compensation between Brg1 and Brm. Brg1 single mutants were healthy and had a normal lifespan, whereas Brg1/Brm double mutants exhibited cardiovascular defects and died within 1 month. BRG1 and BRM were required for the viability of VECs but not other cell types where both genes were also knocked out. The VEC phenotype was most evident in the heart, particularly in the microvasculature of the outer myocardium, and was recapitulated in primary cells ex vivo. VEC death resulted in vascular leakage, cardiac hemorrhage, secondary death of cardiomyocytes due to ischemia, and ventricular dissections.
  
  
  CONCLUSIONS
  BRG1-catalyzed SWI/SNF complexes are particularly important in cardiovascular tissues. However, in contrast to embryonic development, in which Brm does not compensate, Brg1 is required in adult VECs only when Brm is also mutated. These results demonstrate for the first time that Brm functionally compensates for Brg1 in vivo and that there are significant changes in the relative importance of BRG1- and BRM-catalyzed SWI/SNF complexes during the development of an essential cell lineage.
authors: 120 Mason Farm Rd, Genetic Medicine Bldg, Room 5060, Chapel Hill, NC 27516-7264, USA.
authors: Monte S
authors: MS
authors: Willis
authors: Jonathon W
authors: JW
authors: Homeister
authors: Gary B
authors: GB
authors: Rosson
authors: Yunus
authors: Y
authors: Annayev
authors: Darcy
authors: D
authors: Holley
authors: Stephen P
authors: SP
authors: Holly
authors: Victoria J
authors: VJ
authors: Madden
authors: Virginia
authors: V
authors: Godfrey
authors: Leslie V
authors: LV
authors: Parise
authors: Scott J
authors: SJ
authors: Bultman
mesh_terms: D000367:Age Factors; D000818:Animals; D002384:Catalysis; D016923:Cell Death / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D003331:Coronary Vessels / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010996:Pleural Effusion / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; C445179:SWI-SNF-B chromatin-remodeling complex; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases