title: Chromatin remodelling complex dosage modulates transcription factor function in heart development.
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.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.
authors.forename: Jun K
authors.initials: JK
authors.lastname: Takeuchi
authors.forename: Xin
authors.initials: X
authors.lastname: Lou
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Alexander
authors.forename: Hiroe
authors.initials: H
authors.lastname: Sugizaki
authors.forename: Paul
authors.initials: P
authors.lastname: Delgado-Olguín
authors.forename: Alisha K
authors.initials: AK
authors.lastname: Holloway
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Mori
authors.forename: John N
authors.initials: JN
authors.lastname: Wylie
authors.forename: Chantilly
authors.initials: C
authors.lastname: Munson
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Zhou
authors.forename: Ru-Fang
authors.initials: RF
authors.lastname: Yeh
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Pollard
authors.forename: Ian C
authors.initials: IC
authors.lastname: Scott
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D047369:Chromatin Immunoprecipitation; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004452:Echocardiography; D004562:Electrocardiography; D018628:Gene Dosage; D057895:Haploinsufficiency; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000235:genetics*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D046912:Multiprotein Complexes / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D046912:Multiprotein Complexes; C484469:Nkx2-5 protein, mouse; D009687:Nuclear Proteins; C499503:Smarca2 protein, mouse; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; C486013:Tbx20 protein, mouse; D014157:Transcription Factors; D029961:Zebrafish Proteins; C516328:smarca4a protein, zebrafish; C513194:Smarca4 protein, mouse; D004265:DNA Helicases