Proteomics

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Chromatin remodeler Brahma safeguards labile canalization of cardiac mesoderm differentiation


ABSTRACT: Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization. Canalization is essential for stabilizing cell fate, but mechanisms underlying robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite establishment of well-differentiated precardiac mesoderm, Brm-null cells predominantly became 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 referred to as a saddle-node bifurcation. Mechanistically, loss of Brm prevented de novo accessibility of cardiac enhancers while increasing expression of neurogenic factor POU3F1, preventing expression of neural suppressor REST, and disrupting composition of BRG1 complexes. Brm mutant identity switch was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modeling supports all our observations. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1 mutant phenotypes, severely compromising cardiogenesis, unmasking an in vivo role for Brm. Our results reveal Brm as 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Stem Cell

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Ruth Huttenhain  

LAB HEAD: Ruth Huttenhain

PROVIDER: PXD026638 | Pride | 2021-11-03

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
202011_uniprot_reviewed_mus_musculus.fasta Fasta
SH95-136_keys.txt Txt
allPeptides.txt Txt
checksum.txt Txt
evidence.txt Txt
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Publications


Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization<sup>1,2</sup>. 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  ...[more]

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