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Chromatin remodelling complex dosage modulates transcription factor function in heart development.

Nature communications | Feb 8, 2011

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.

Pubmed ID: 21304516 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Animals | Chromatin Immunoprecipitation | DNA Helicases | DNA Primers | Echocardiography | Electrocardiography | Gene Dosage | Haploinsufficiency | Heart | Heart Defects, Congenital | Homeobox Protein Nkx-2.5 | Homeodomain Proteins | Mice | Microarray Analysis | Morphogenesis | Multiprotein Complexes | NIH 3T3 Cells | Nuclear Proteins | T-Box Domain Proteins | Transcription Factors | Zebrafish | Zebrafish Proteins

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Associated grants

  • Agency: NHLBI NIH HHS, Id: R01 HL085860
  • Agency: NHLBI NIH HHS, Id: R01 HL085860-05
  • Agency: Canadian Institutes of Health Research, Id: 86663
  • Agency: NHLBI NIH HHS, Id: R01 HL054737
  • Agency: NHLBI NIH HHS, Id: R01 HL54737
  • Agency: NCRR NIH HHS, Id: C06 RR018928

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