ATACseq of WT and BRM KO cells at D4, D6 and D10 of cardiac differentiation

ABSTRACT: We performed ATAC-seq on WT, BAF60c KO, BAF170 KO and BRM KO CPs and CMs in 2-5 biological replicates follwing Corces et al., 2017 paper. Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization How robust canalization is established or maintained is 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 saddle-node bifurcation. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE150180 | GEO | 2021/10/27

REPOSITORIES: GEO