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PMID:21304516

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Citation

Takeuchi, JK, Lou, X, Alexander, JM, Sugizaki, H, Delgado-Olguín, P, Holloway, AK, Mori, AD, Wylie, JN, Munson, C, Zhu, Y, Zhou, YQ, Yeh, RF, Henkelman, RM, Harvey, RP, Metzger, D, Chambon, P, Stainier, DY, Pollard, KS, Scott, IC and Bruneau, BG (2011) Chromatin remodelling complex dosage modulates transcription factor function in heart development. Nat Commun 2:187

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.

Links

PubMed PMC3096875 Online version:10.1038/ncomms1187

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:Q6NZ27

involved_in

GO:0001947: heart looping

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110315-8

P

Seeded From UniProt

complete

DANRE:Q6NZ27

involved_in

GO:0060038: cardiac muscle cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110315-8

P

Seeded From UniProt

complete

DANRE:Q6NZ27

involved_in

GO:0060973: cell migration involved in heart development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110315-8

P

Seeded From UniProt

complete

DANRE:Q7ZSY3

involved_in

GO:0001947: heart looping

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110315-8

P

Seeded From UniProt

complete

DANRE:Q7ZSY3

involved_in

GO:0060038: cardiac muscle cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110315-8

P

Seeded From UniProt

complete

DANRE:Q7ZSY3

involved_in

GO:0060973: cell migration involved in heart development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110315-8

P

Seeded From UniProt

complete

DANRE:Q803N3

involved_in

GO:0001947: heart looping

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110315-8

P

Seeded From UniProt

complete

DANRE:Q803N3

involved_in

GO:0060038: cardiac muscle cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110315-8

P

Seeded From UniProt

complete

DANRE:Q803N3

involved_in

GO:0060973: cell migration involved in heart development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110315-8

P

Seeded From UniProt

complete


See also

References

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