期刊
CELL REPORTS
卷 30, 期 2, 页码 465-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.12.039
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资金
- National Eye Institute [K08EY026654]
- National Cancer Institute [P30CA046592]
- Research to Prevent Blindness
- Beatrice & Reymont Paul Foundation
- March Hoops to Beat Blindness
- Taubman Institute
- Leonard G. Miller Endowed Professorship
- Ophthalmic Research Fund at the Kellogg Eye Center
- Grossman research fund
- Elaine Sandman research fund
- Marek and Maria Spatz (endowed) research fund
- Greenspon research fund
- Dunn research fund
- Avers research fund
- Boustikakis research fund
- Sweiden research fund
- Terauchi research fund
How ubiquitous transcription factors (TFs) coordinate temporal inputs from broadly expressed epigenetic factors to control cell fate remains poorly understood. Here, we uncover a molecular relationship between p53, an abundant embryonic TF, and WDR5, an essential member of the MLL chromatin modifying complex, that regulates mouse embryonic stem cell fate. Wild-type Wdr5 or transient Wdr5 knockout promotes a distinct pattern of global chromatin accessibility and spurs neuroectodermal differentiation through an RbBP5-dependent process in which WDR5 binds to, and activates transcription of, neural genes. Wdr5 rescue after its prolonged inhibition targets WDR5 to mesoderm lineage-specifying genes, stimulating differentiation toward mesoderm fates in a p53-dependent fashion. Finally, we identify a direct interaction between WDR5 and p53 that enables their co-recruitment to, and regulation of, genes known to control cell proliferation and fate. Our results unmask p53-dependent mechanisms that temporally integrate epigenetic WDR5 inputs to drive neuroectoderm and mesoderm differentiation from pluripotent cells.
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