p53 Integrates Temporal WDR5 Inputs during Neuroectoderm and Mesoderm Differentiation of Mouse Embryonic Stem Cells

Qiang Li; Fengbiao Mao; Bo Zhou; Yuanhao Huang; Zhenhua Zou; Aaron D denDekker; Jing Xu; Sean Hou; Jie Liu; Yali Dou; Rajesh C Rao

doi:10.1016/j.celrep.2019.12.039

p53 Integrates Temporal WDR5 Inputs during Neuroectoderm and Mesoderm Differentiation of Mouse Embryonic Stem Cells

Cell Rep. 2020 Jan 14;30(2):465-480.e6. doi: 10.1016/j.celrep.2019.12.039.

Authors

Qiang Li¹, Fengbiao Mao², Bo Zhou³, Yuanhao Huang⁴, Zhenhua Zou², Aaron D denDekker³, Jing Xu³, Sean Hou¹, Jie Liu⁴, Yali Dou⁵, Rajesh C Rao⁶

Affiliations

¹ Department of Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, MI, USA.
² Department of Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
³ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; Taubman Institute, University of Michigan, Ann Arbor, MI, USA; Section of Ophthalmology, Surgical Service, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI, USA. Electronic address: rajeshr@umich.edu.

Abstract

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.

Keywords: WDR5; cardiomyocyte; cell fate; chromatin; differentiation; embryonic stem cells; mesoderm; neuroectoderm; p53; retina.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Humans
Intracellular Signaling Peptides and Proteins / metabolism*
Mesoderm / physiology*
Mice
Mouse Embryonic Stem Cells / metabolism*
Neural Plate / physiology*
Tumor Suppressor Protein p53 / metabolism*

Substances

Intracellular Signaling Peptides and Proteins
Tumor Suppressor Protein p53
Wdr5 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding