BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease

Joaquim Miguel Vieira, Sara Howard, Cristina Villa del Campo, Sveva Bollini, Karina N. Dubé, Megan Masters, Damien N. Barnette, Mala Rohling, Xin Sun, Laura E. Hankins, Daria Gavriouchkina, Ruth Williams, Daniel Metzger, Pierre Chambon, Tatjana Sauka-Spengler, Benjamin Davies and Paul R. Riley ()
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Joaquim Miguel Vieira: Burdon Sanderson Cardiac Science Centre, Anatomy and Genetics, University of Oxford
Sara Howard: Molecular Medicine Unit, UCL Institute of Child Health
Cristina Villa del Campo: Burdon Sanderson Cardiac Science Centre, Anatomy and Genetics, University of Oxford
Sveva Bollini: Burdon Sanderson Cardiac Science Centre, Anatomy and Genetics, University of Oxford
Karina N. Dubé: Molecular Medicine Unit, UCL Institute of Child Health
Megan Masters: Burdon Sanderson Cardiac Science Centre, Anatomy and Genetics, University of Oxford
Damien N. Barnette: Burdon Sanderson Cardiac Science Centre, Anatomy and Genetics, University of Oxford
Mala Rohling: Burdon Sanderson Cardiac Science Centre, Anatomy and Genetics, University of Oxford
Xin Sun: Burdon Sanderson Cardiac Science Centre, Anatomy and Genetics, University of Oxford
Laura E. Hankins: Burdon Sanderson Cardiac Science Centre, Anatomy and Genetics, University of Oxford
Daria Gavriouchkina: Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
Ruth Williams: Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
Daniel Metzger: Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964/CNRS UMR 7104/Université de Strasbourg
Pierre Chambon: Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964/CNRS UMR 7104/Université de Strasbourg
Tatjana Sauka-Spengler: Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
Benjamin Davies: Wellcome Trust Centre for Human Genetics, University of Oxford
Paul R. Riley: Burdon Sanderson Cardiac Science Centre, Anatomy and Genetics, University of Oxford

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Epicardium-derived cells (EPDCs) contribute cardiovascular cell types during development and in adulthood respond to Thymosin β4 (Tβ4) and myocardial infarction (MI) by reactivating a fetal gene programme to promote neovascularization and cardiomyogenesis. The mechanism for epicardial gene (re-)activation remains elusive. Here we reveal that BRG1, the essential ATPase subunit of the SWI/SNF chromatin–remodelling complex, is required for expression of Wilms’ tumour 1 (Wt1), fetal EPDC activation and subsequent differentiation into coronary smooth muscle, and restores Wt1 activity upon MI. BRG1 physically interacts with Tβ4 and is recruited by CCAAT/enhancer-binding protein β (C/EBPβ) to discrete regulatory elements in the Wt1 locus. BRG1-Tβ4 co-operative binding promotes optimal transcription of Wt1 as the master regulator of embryonic EPDCs. Moreover, chromatin immunoprecipitation-sequencing reveals BRG1 binding at further key loci suggesting SWI/SNF activity across the fetal epicardial gene programme. These findings reveal essential functions for chromatin–remodelling in the activation of EPDCs during cardiovascular development and repair.

Date: 2017
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DOI: 10.1038/ncomms16034

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