p53 inactivation unmasks histone methylation-independent WDR5 functions that drive self-renewal and differentiation of pluripotent stem cells

Qiang Li; Yuanhao Huang; Jing Xu; Fengbiao Mao; Bo Zhou; Lichao Sun; Brian W Basinski; Michael Aksu; Jie Liu; Yali Dou; Rajesh C Rao

doi:10.1016/j.stemcr.2021.10.002

p53 inactivation unmasks histone methylation-independent WDR5 functions that drive self-renewal and differentiation of pluripotent stem cells

Stem Cell Reports. 2021 Nov 9;16(11):2642-2658. doi: 10.1016/j.stemcr.2021.10.002. Epub 2021 Oct 28.

Authors

Qiang Li¹, Yuanhao Huang², Jing Xu¹, Fengbiao Mao³, Bo Zhou³, Lichao Sun³, Brian W Basinski⁴, Michael Aksu¹, Jie Liu⁵, Yali Dou⁶, Rajesh C Rao⁷

Affiliations

¹ Department of Ophthalmology & Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall St., Ann Arbor, MI 48105, USA.
² Department and Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
³ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Ophthalmology & Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall St., Ann Arbor, MI 48105, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁵ Department and Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Ophthalmology & Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall St., Ann Arbor, MI 48105, USA; Department and Center of Computational Medicine and Bioinformatics, 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; A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, MI, USA; Center for RNA Biomedicine, University of Michigan, Ann Arbor, MI, USA; Division of Ophthalmology, Surgery Section, VA Ann Arbor Healthsystem, Ann Arbor, MI, USA. Electronic address: rajeshr@umich.edu.

Abstract

p53 alterations occur during culture of pluripotent stem cells (PSCs), but the significance of these events on epigenetic control of PSC fate determination remains poorly understood. Wdr5 deletion in p53-null (DKO) mouse ESCs (mESCs) leads to impaired self-renewal, defective retinal neuroectoderm differentiation, and de-repression of germ cell/meiosis (GCM)-specific genes. Re-introduction of a WDR5 mutant with defective H3K4 methylation activity into DKO ESCs restored self-renewal and suppressed GCM gene expression but failed to induce retinal neuroectoderm differentiation. Mechanistically, mutant WDR5 targets chromatin that is largely devoid of H3K4me3 and regulates gene expression in p53-null mESCs. Furthermore, MAX and WDR5 co-target lineage-specifying chromatin and regulate chromatin accessibility of GCM-related genes. Importantly, MAX and WDR5 are core subunits of a non-canonical polycomb repressor complex 1 responsible for gene silencing. This function, together with canonical, pro-transcriptional WDR5-dependent MLL complex H3K4 methyltransferase activity, highlight how WDR5 mediates crosstalk between transcription and repression during mESC fate choice.

Keywords: MAX; WDR5; chromatin; embryonic stem cells; germ cell; meiosis; neuroectoderm; p53; retina; stem cells.

Publication types

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

MeSH terms

Animals
Cell Differentiation / genetics*
Cell Line
Cell Self Renewal / genetics*
Chromatin / genetics
Chromatin / metabolism
Chromatin Immunoprecipitation Sequencing / methods
Gene Expression Profiling / methods
Histones / metabolism*
Intracellular Signaling Peptides and Proteins / genetics*
Intracellular Signaling Peptides and Proteins / metabolism
Methylation
Mice
Mice, Knockout
Mice, Transgenic
Mouse Embryonic Stem Cells / metabolism*
Pluripotent Stem Cells / metabolism*
RNA-Seq / methods
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding