Chromatin Remodelling Complex Dosage Modulates Transcription Factor Function in Heart Development

Overview

Journal Nat Commun

Specialty Biology

Date 2011 Feb 10

PMID 21304516

Citations 115

Authors

Jun K Takeuchi

Xin Lou

Jeffrey M Alexander

Hiroe Sugizaki

Paul Delgado-Olguin

Alisha K Holloway

Alessandro D Mori

John N Wylie

Chantilly Munson

Yonghong Zhu

Yu-Qing Zhou

Ru-Fang Yeh

R Mark Henkelman

Richard P Harvey

Daniel Metzger

Pierre Chambon

Didier Y R Stainier

Katherine S Pollard

Ian C Scott

Benoit G Bruneau

Affiliations

Soon will be listed here.

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.

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