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p53 Coordinates Temporal WDR5 Inputs During Neuroectoderm and Mesoderm Differentiation of Mouse Embryonic Stem Cells

54 Pages Posted: 4 Jan 2019 Publication Status: Under Review

See all articles by Qiang Li

Qiang Li

University of Michigan at Ann Arbor - Department of Opthalmology and Visual Sciences

Fengbiao Mao

University of Michigan at Ann Arbor - Department of Pathology

Zhenhua Zou

University of Michigan at Ann Arbor - Department of Opthalmology and Visual Sciences

Aaron DenDekker

University of Michigan at Ann Arbor - Department of Pathology

Jing Xu

University of Michigan at Ann Arbor - Department of Pathology

Sean Hou

University of Michigan at Ann Arbor - Department of Opthalmology and Visual Sciences

Yali Dou

University of Michigan at Ann Arbor - Department of Pathology

Rajesh C. Rao

University of Michigan at Ann Arbor - Department of Opthalmology and Visual Sciences

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Abstract

Cell-type specific transcription factors cooperate with chromatin-modifying proteins to orchestrate proper differentiation, but little is known how ubiquitous embryonic proteins coordinate inputs from broadly expressed epigenetic factors to control cell fate. Here, we uncover a previously unappreciated molecular relationship between p53, an abundant embryonic protein, and Wdr5, an essential member of the COMPASS chromatin modifying complex, that regulates mouse embryonic stem cell (ESC) fate. Intact, or brief disruption of, Wdr5 activity promotes a distinct pattern of global chromatin accessibility and spurs neuroectodermal specification through Wdr5 binding to, and transcription of, neural genes. This leads to RbBP5-dependent differentiation of 3D Rx+ neuroectodermal organoids. In contrast, prolonged Wdr5 inhibition transcriptionally impairs ribosome biogenesis, which upregulates p53 activity, triggering increased expression of pro-mesoderm p53 target genes and emergence of a chromatin accessibility state permissive for mesoderm specification. Rescue of Wdr5 function after its extended inhibition targets WDR5 to mesoderm lineage-specifying genes, stimulating differentiation toward contractile cardiogenic and hematopoietic mesoderm fates. This cell fate transition is p53-dependent, as p53 inactivation partially rescues neuroectoderm differentiation and inhibits mesoderm formation. Our results unmask a p53-dependent mechanism that temporally integrates an epigenetic WDR5 input to drive neuroectoderm and mesoderm differentiation from pluripotent cells.

Suggested Citation

Li, Qiang and Mao, Fengbiao and Zou, Zhenhua and DenDekker, Aaron and Xu, Jing and Hou, Sean and Dou, Yali and Rao, Rajesh C., p53 Coordinates Temporal WDR5 Inputs During Neuroectoderm and Mesoderm Differentiation of Mouse Embryonic Stem Cells (December 29, 2018). Available at SSRN: https://ssrn.com/abstract=3307529 or http://dx.doi.org/10.2139/ssrn.3307529
This version of the paper has not been formally peer reviewed.

Qiang Li (Contact Author)

University of Michigan at Ann Arbor - Department of Opthalmology and Visual Sciences

Ann Arbor, MI
United States

Fengbiao Mao

University of Michigan at Ann Arbor - Department of Pathology

Ann Arbor, MI 48109,
United States

Zhenhua Zou

University of Michigan at Ann Arbor - Department of Opthalmology and Visual Sciences

Ann Arbor, MI
United States

Aaron DenDekker

University of Michigan at Ann Arbor - Department of Pathology

Ann Arbor, MI 48109,
United States

Jing Xu

University of Michigan at Ann Arbor - Department of Pathology

Ann Arbor, MI 48109,
United States

Sean Hou

University of Michigan at Ann Arbor - Department of Opthalmology and Visual Sciences

Ann Arbor, MI
United States

Yali Dou

University of Michigan at Ann Arbor - Department of Pathology

Ann Arbor, MI 48109,
United States

Rajesh C. Rao

University of Michigan at Ann Arbor - Department of Opthalmology and Visual Sciences ( email )

Ann Arbor, MI
United States

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