Brahma safeguards canalization of cardiac mesoderm differentiation
Autor: | 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, Benoit G. Bruneau |
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Rok vydání: | 2022 |
Předmět: |
Male
animal structures Time Factors General Science & Technology Neurogenesis 1.1 Normal biological development and functioning Bone Morphogenetic Protein 4 Article Epigenesis Genetic Mesoderm Mice Genetic Underpinning research Genetics Animals Myocytes Cardiac Cell Lineage Neurons Myocytes Multidisciplinary Myocardium Stem Cells Mammalian DNA Helicases Nuclear Proteins Cell Differentiation Embryo Mammalian Chromatin Assembly and Disassembly Stem Cell Research Chromatin Repressor Proteins Phenotype Gene Expression Regulation Embryo Octamer Transcription Factor-6 Female Stem Cell Research - Nonembryonic - Non-Human Cardiac Transcription Factors Epigenesis |
Zdroj: | Nature, vol 602, iss 7895 Nature |
Popis: | 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. |
Databáze: | OpenAIRE |
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