PUBLICATION

Chromatin remodelling complex dosage modulates transcription factor function in heart development

Authors
Takeuchi, J.K., Lou, X., Alexander, J.M., Sugizaki, H., Delgado-Olguín, P., Holloway, A.K., Mori, A.D., Wylie, J.N., Munson, C., Zhu, Y., Zhou, Y.Q., Yeh, R.F., Henkelman, R.M., Harvey, R.P., Metzger, D., Chambon, P., Stainier, D.Y., Pollard, K.S., Scott, I.C., and Bruneau, B.G.
ID
ZDB-PUB-110214-21
Date
2011
Source
Nature communications   2: 187 (Journal)
Registered Authors
Chambon, Pierre, Stainier, Didier
Keywords
none
MeSH Terms
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Chromatin Immunoprecipitation
  • DNA Helicases/genetics
  • DNA Helicases/metabolism*
  • DNA Primers/genetics
  • Echocardiography
  • Electrocardiography
  • Gene Dosage
  • Haploinsufficiency
  • Heart/embryology*
  • Heart Defects, Congenital/genetics*
  • Homeodomain Proteins/metabolism
  • Mice
  • Microarray Analysis
  • Morphogenesis/genetics
  • Morphogenesis/physiology*
  • Multiprotein Complexes/metabolism*
  • NIH 3T3 Cells
  • Nuclear Proteins/genetics
  • Nuclear Proteins/metabolism*
  • T-Box Domain Proteins/metabolism
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
21304516 Full text @ Nat. Commun.
Abstract
Dominant mutations in cardiac transcription factor genes cause human inherited congenital heart defects (CHDs); however, their molecular basis is not understood. Interactions between transcription factors and the Brg1/Brm-associated factor (BAF) chromatin remodelling complex suggest potential mechanisms; however, the role of BAF complexes in cardiogenesis is not known. In this study, we show that dosage of Brg1 is critical for mouse and zebrafish cardiogenesis. Disrupting the balance between Brg1 and disease-causing cardiac transcription factors, including Tbx5, Tbx20 and Nkx2-5, causes severe cardiac anomalies, revealing an essential allelic balance between Brg1 and these cardiac transcription factor genes. This suggests that the relative levels of transcription factors and BAF complexes are important for heart development, which is supported by reduced occupancy of Brg1 at cardiac gene promoters in Tbx5 haploinsufficient hearts. Our results reveal complex dosage-sensitive interdependence between transcription factors and BAF complexes, providing a potential mechanism underlying transcription factor haploinsufficiency, with implications for multigenic inheritance of CHDs.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes