p53 inactivation unmasks histone methylation-independent WDR5 functions that drive self-renewal and differentiation of pluripotent stem cells
| Autor: | Michael Aksu, Jie Liu, Rajesh C. Rao, Bo Zhou, Qiang Li, Yali Dou, Yuanhao Huang, Fengbiao Mao, Jing Xu, Lichao Sun, Brian W. Basinski |
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| Rok vydání: | 2021 |
| Předmět: |
p53
Pluripotent Stem Cells retina WDR5 Mice Transgenic Biology Methylation Biochemistry Article Cell Line Histones Mice stem cells Histone methylation Genetics medicine meiosis Animals RNA-Seq Epigenetics Cell Self Renewal Induced pluripotent stem cell Mice Knockout neuroectoderm Neuroectoderm Gene Expression Profiling Intracellular Signaling Peptides and Proteins Cell Differentiation Mouse Embryonic Stem Cells germ cell Cell Biology embryonic stem cells Embryonic stem cell Chromatin Cell biology medicine.anatomical_structure Chromatin Immunoprecipitation Sequencing Tumor Suppressor Protein p53 Germ cell MAX Developmental Biology |
| Zdroj: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| DOI: | 10.1016/j.stemcr.2021.10.002 |
| Popis: | Summary 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. Graphical abstract Highlights • H3K4me defective WDR5 supports self-renewal and GCM differentiation in p53-null mESCs • WDR5 regulates H3K4me-independent stemness and GCM gene expression in p53-null mESCs • MAX and WDR5 repress GCM-related gene chromatin accessibility upon differentiation In this article, Rao and colleagues show that an H3K4 methylation-independent, WDR5-driven mechanism maintains self-renewal and represses germ cell/meiosis (GCM)-specific transcription in p53-null mESCs. WDR5 inactivation triggers enhanced chromatin accessibility on most gene targets bound by MAX and WDR5. Thus, WDR5, a component of polycomb repressive complex 1.6, controls cell type-specific gene repression during mESC fate determination in a non-canonical fashion. |
| Databáze: | OpenAIRE |
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