Functional redundancy of SWI/SNF catalytic subunits in maintaining vascular endothelial cells in the adult heart

Monte S. Willis, Jonathon W. Homeister, Gary B. Rosson, Yunus Annayev, Darcy Holley, Stephen P. Holly, Victoria J. Madden, Virginia Godfrey, Leslie V. Parise, Scott J. Bultman

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Rationale: 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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)e111-e122
JournalCirculation research
Volume111
Issue number5
DOIs
StatePublished - Aug 17 2012

Fingerprint

Sucrose
Catalytic Domain
Endothelial Cells
Embryonic Development
Phenotype
Chromatin Assembly and Disassembly
Gene Targeting
Nucleosomes
Cell Lineage
Microvessels
Cardiac Myocytes
Blood Vessels
Dissection
Myocardium
Cell Death
Ischemia
Hemorrhage
Gene Expression
Genes

Keywords

  • BRG1
  • BRM
  • SWI/SNF
  • cardiac vascular endothelial cell
  • conditional transgenic mouse
  • endothelial dysfunction
  • epigenetics
  • genetics
  • ventricular dissection

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Functional redundancy of SWI/SNF catalytic subunits in maintaining vascular endothelial cells in the adult heart. / Willis, Monte S.; Homeister, Jonathon W.; Rosson, Gary B.; Annayev, Yunus; Holley, Darcy; Holly, Stephen P.; Madden, Victoria J.; Godfrey, Virginia; Parise, Leslie V.; Bultman, Scott J.

In: Circulation research, Vol. 111, No. 5, 17.08.2012, p. e111-e122.

Research output: Contribution to journalArticle

Willis, MS, Homeister, JW, Rosson, GB, Annayev, Y, Holley, D, Holly, SP, Madden, VJ, Godfrey, V, Parise, LV & Bultman, SJ 2012, 'Functional redundancy of SWI/SNF catalytic subunits in maintaining vascular endothelial cells in the adult heart', Circulation research, vol. 111, no. 5, pp. e111-e122. https://doi.org/10.1161/CIRCRESAHA.112.265587
Willis, Monte S. ; Homeister, Jonathon W. ; Rosson, Gary B. ; Annayev, Yunus ; Holley, Darcy ; Holly, Stephen P. ; Madden, Victoria J. ; Godfrey, Virginia ; Parise, Leslie V. ; Bultman, Scott J. / Functional redundancy of SWI/SNF catalytic subunits in maintaining vascular endothelial cells in the adult heart. In: Circulation research. 2012 ; Vol. 111, No. 5. pp. e111-e122.
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abstract = "Rationale: 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. Methods and 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.",
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AU - Rosson, Gary B.

AU - Annayev, Yunus

AU - Holley, Darcy

AU - Holly, Stephen P.

AU - Madden, Victoria J.

AU - Godfrey, Virginia

AU - Parise, Leslie V.

AU - Bultman, Scott J.

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N2 - Rationale: 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. Methods and 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.

AB - Rationale: 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. Methods and 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.

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KW - ventricular dissection

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