1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
2. Cardiovascular Research and Developmental Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
3. Mouse Imaging Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
4. Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario M5S 1A8, Canada
5. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
6. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
7. University College Dublin, Department of Obstetrics & Gynaecology, National Maternity Hospital, Holles Street, Dublin 2, Ireland
8. Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario M5G 1L4, Canada
9. These authors contributed equally to this work

Correspondence to: Janet Rossant^1,8Benoit G. Bruneau^2,3,8 Email: bbruneau@sickkids.ca
Email: rossant@mshri.on.ca

Abstract

Tissue-specific transcription factors regulate several important aspects of embryonic development. They must function in the context of DNA assembled into the higher-order structure of chromatin. Enzymatic complexes such as the Swi/Snf-like BAF complexes remodel chromatin to allow the transcriptional machinery access to gene regulatory elements^{1, 2}. Here we show that Smarcd3, encoding Baf60c, a subunit of the BAF complexes, is expressed specifically in the heart and somites in the early mouse embryo. Smarcd3 silencing by RNA interference in mouse embryos derived from embryonic stem cells causes defects in heart morphogenesis that reflect impaired expansion of the anterior/secondary heart field, and also results in abnormal cardiac and skeletal muscle differentiation. An intermediate reduction in Smarcd3 expression leads to defects in outflow tract remodelling reminiscent of human congenital heart defects. Baf60c overexpressed in cell culture can mediate interactions between cardiac transcription factors and the BAF complex ATPase Brg1, thereby potentiating the activation of target genes. These results reveal tissue-specific and dose-dependent roles for Baf60c in recruiting BAF chromatin remodelling complexes to heart-specific enhancers, providing a novel mechanism to ensure transcriptional regulation during organogenesis.

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