Chromatin Remodeling Complex Dosage Modulates Transcription Factor Function in Heart Development

Dominant mutations in cardiac transcription factor genes cause human inherited congenital heart defects (CHDs), but their molecular basis is not understood. Transcription factors and Brg1/Brm-associated factor (BAF) chromatin remodeling complex interactions suggest potential mechanisms, but the role of BAF complexes in cardiogenesis is not known. Here 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 relative levels of transcription factors and BAF complexes are important for heart development, which is supported by reduced occupancy of Brg1 at cardiac genes 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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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, Bruneau BG