Brahma safeguards canalization of cardiac mesoderm differentiation

Swetansu K. Hota (), Kavitha S. Rao, Andrew P. Blair, Ali Khalilimeybodi, Kevin M. Hu, Reuben Thomas, Kevin So, Vasumathi Kameswaran, Jiewei Xu, Benjamin J. Polacco, Ravi V. Desai, Nilanjana Chatterjee, Austin Hsu, Jonathon M. Muncie, Aaron M. Blotnick, Sarah A. B. Winchester, Leor S. Weinberger, Ruth Hüttenhain, Irfan S. Kathiriya, Nevan J. Krogan, Jeffrey J. Saucerman and Benoit G. Bruneau ()
Additional contact information
Swetansu K. Hota: Gladstone Institutes
Kavitha S. Rao: Gladstone Institutes
Andrew P. Blair: Gladstone Institutes
Ali Khalilimeybodi: University of Virginia
Kevin M. Hu: Gladstone Institutes
Reuben Thomas: Gladstone Institutes
Kevin So: Gladstone Institutes
Vasumathi Kameswaran: Gladstone Institutes
Jiewei Xu: Gladstone Institutes
Benjamin J. Polacco: Gladstone Institutes
Ravi V. Desai: Gladstone Institutes
Nilanjana Chatterjee: University of California
Austin Hsu: Gladstone Institutes
Jonathon M. Muncie: Gladstone Institutes
Aaron M. Blotnick: Gladstone Institutes
Sarah A. B. Winchester: Gladstone Institutes
Leor S. Weinberger: Gladstone Institutes
Ruth Hüttenhain: Gladstone Institutes
Irfan S. Kathiriya: Gladstone Institutes
Nevan J. Krogan: Gladstone Institutes
Jeffrey J. Saucerman: University of Virginia
Benoit G. Bruneau: Gladstone Institutes

Nature, 2022, vol. 602, issue 7895, 129-134

Abstract: Abstract Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1,2. Canalization is essential for stabilizing cell fate, but the mechanisms that underlie robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin-remodelling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite the establishment of a well-differentiated precardiac mesoderm, Brm−/− cells predominantly became neural precursors, violating germ layer assignment. Trajectory inference showed a sudden acquisition of a non-mesodermal identity in Brm−/− cells. Mechanistically, the loss of Brm prevented de novo accessibility of primed cardiac enhancers while increasing the expression of neurogenic factor POU3F1, preventing the binding of the neural suppressor REST and shifting the composition of BRG1 complexes. The identity switch caused by the Brm mutation was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modelling supports these observations and demonstrates that Brm deletion affects cell fate trajectory by modifying saddle–node bifurcations2. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1-mutant phenotypes, severely compromising cardiogenesis, and reveals an in vivo role for Brm. Our results show that Brm is a compensable safeguard of the fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory.

Date: 2022
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DOI: 10.1038/s41586-021-04336-y

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