RT Journal Article SR Electronic T1 Chromatin remodeler Brahma safeguards canalization in cardiac mesoderm differentiation JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.06.03.132654 DO 10.1101/2020.06.03.132654 A1 Swetansu K. Hota A1 Andrew P. Blair A1 Kavitha S. Rao A1 Kevin So A1 Aaron M. Blotnick A1 Ravi V. Desai A1 Leor S. Weinberger A1 Irfan S. Kathiriya A1 Benoit G. Bruneau YR 2020 UL http://biorxiv.org/content/early/2020/06/04/2020.06.03.132654.abstract AB Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1–4. Canalization is essential for stabilizing cell fate, but the mechanisms underlying robust canalization are unclear. Here we show that deletion of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex ATPase gene Brm (encoding Brahma) results in a radical identity switch during directed cardiogenesis of mouse embryonic stem cells (ESCs). Despite establishment of well-differentiated precardiac mesoderm, Brm-null cells subsequently shifted identities, predominantly becoming neural precursors, violating germ layer assignment. Trajectory inference showed sudden acquisition of non-mesodermal identity in Brm-null cells, consistent with a new transition state inducing a fate switch referred to as a saddle-node bifurcation3,4. Mechanistically, loss of Brm prevented de novo accessibility of cardiac enhancers while increasing expression of the neurogenic factor POU3F1 and preventing expression of the neural suppressor REST. Brm mutant identity switch was overcome by increasing BMP4 levels during mesoderm induction, repressing Pou3f1 and re-establishing a cardiogenic chromatin landscape. Our results reveal BRM as a compensable safeguard for fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory that must be safeguarded, with implications in development and disease.Competing Interest StatementThe authors have declared no competing interest.