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WDR5 Remodels NANOG Condensates to Drive Transcriptional Programs and Sustain Stem Cell Identity

ABSTRACT: Stem cell pluripotency relies on a finely tuned interplay between transcription factors and epigenetic regulators. Here, we identify a direct interaction between NANOG, a master pluripotency transcription factor, and WDR5, a core component of the SET1/MLL complex that is essential for maintaining stem cell identity. Mechanistically, WDR5 reshapes the prion-like structures of NANOG into dynamic, liquid-liquid phase-separated (LLPS) condensates, facilitating its recruitment to pluripotency-associated promoters and activating target gene expression. X-ray crystallography and NMR spectroscopy reveal that the NANOG homeodomain engages WDR5 through an extensive structural interface distinct from previously characterized short linear motifs. The NANOGR153A mutation disrupts its interaction with WDR5, leading to impaired LLPS formation, reduced chromatin co-occupancy, and diminished levels of active histone marks (H3K4me3 and H4K16ac), ultimately compromising the pluripotency of embryonic stem cells. Furthermore, pharmacological inhibition of the WDR5-NANOG interaction using a WIN motif inhibitor robustly suppresses leukemia stem cell expansion in vivo, highlighting its therapeutic potential. Collectively, this study uncovers an LLPS-mediated regulatory mechanism whereby WDR5 modulates NANOG condensate dynamics to sustain stem cell identity in both physiological and pathological contexts.

ORGANISM(S): Mus musculus

PROVIDER: GSE297660 | GEO | 2025/11/19

REPOSITORIES: GEO

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Project description:Chickarmane2008 - Stem cell lineage - NANOG GATA-6 switch In this work, a dynamical model of lineage determination based upon a minimal circuit, as discussed in PMID: 17215298 , which contains the Oct4/Sox2/Nanog core as well its interaction with a few other key genes is discussed. This model is described in the article: A computational model for understanding stem cell, trophectoderm and endoderm lineage determination. Chickarmane V, Peterson C PloS one. 2008, 3(10):e3478 Abstract: BACKGROUND: Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4. METHODOLOGY/ PRINCIPAL FINDINGS: We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions; activation of Gata-6 by Oct4 and repression of Nanog by an Oct4-Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6. CONCLUSIONS: The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state. This model is hosted on BioModels Database and identified by: MODEL8389825246 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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WDR5 Remodels NANOG Condensates to Drive Transcriptional Programs and Sustain Stem Cell Identity

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