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

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

doi:10.1016/j.celrep.2019.12.039

Cited by 20 publications

(21 citation statements)

References 60 publications

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“…We thus conducted RNA-sequencing using 9-day-old EBs, in which WT and KO cells commit to the similar lineage. Global comparisons using principle components analysis (PCA) and hierarchical clustering analysis revealed that EB replicates in the same group had high reproducibility, and that their identity was close to previously reported neuroectoderm organoids 33 than to other developmental derivatives 34,35 ( Supplementary Fig. 4e, f).…”

Section: Fgf8supporting

confidence: 64%

STRAP regulates alternative splicing fidelity during lineage commitment of mouse embryonic stem cells

et al. 2020

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Alternative splicing (AS) is involved in cell fate decisions and embryonic development. However, regulation of these processes is poorly understood. Here, we have identified the serine threonine kinase receptor-associated protein (STRAP) as a putative spliceosome-associated factor. Upon Strap deletion, there are numerous AS events observed in mouse embryoid bodies (EBs) undergoing a neuroectoderm-like state. Global mapping of STRAP-RNA binding in mouse embryos by enhanced-CLIP sequencing (eCLIP-seq) reveals that STRAP preferably targets transcripts for nervous system development and regulates AS through preferred binding positions, as demonstrated for two neuronal-specific genes, Nnat and Mark3. We have found that STRAP involves in the assembly of 17S U2 snRNP proteins. Moreover, in Xenopus, loss of Strap leads to impeded lineage differentiation in embryos, delayed neural tube closure, and altered exon skipping. Collectively, our findings reveal a previously unknown function of STRAP in mediating the splicing networks of lineage commitment, alteration of which may be involved in early embryonic lethality in mice.

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Section: Fgf8supporting

confidence: 64%

STRAP regulates alternative splicing fidelity during lineage commitment of mouse embryonic stem cells

et al. 2020

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“…At day 4, cells were counted using Trypan Blue dye, centrifuged at 211 xg and washed with Ca ++ and Mg ++ free 1X DPBS (14190144, Gibco™). 2 × 10 6 viable cells per sample per antibody were processed for CUT&RUN experiment as previously described 46 . Briefly, cells were collected and washed by PBS at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity

Rogawski

Deng

et al. 2021

Nat Commun

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ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.

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“…Like WDR5, p53 is highly expressed in ESCs and decreases during differentiation (Lin et al, 2005). We found that WDR5 interacts with p53 (Li et al, 2020). We identified a repressor function for WDR5, in which its transient inhibition triggers mESC misspecification toward the mesoderm lineage under conditions that normally induce neuroectoderm fate, through a p53-dependent mechanism (Li et al, 2020).…”

Section: Introductionmentioning

confidence: 83%

“…We found that WDR5 interacts with p53 (Li et al, 2020). We identified a repressor function for WDR5, in which its transient inhibition triggers mESC misspecification toward the mesoderm lineage under conditions that normally induce neuroectoderm fate, through a p53-dependent mechanism (Li et al, 2020). p53 is most recognized as a regulator of DNA damage and aberrant p53 loss-of-function and gain-of-function (GoF) mutations contribute to tumorigenesis (Giaccia and Kastan, 1998;Haupt et al, 1997;Sabapathy et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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

Abstract: Highlights d WDR5-RbBP5 interaction surface controls ESC-toneuroectoderm organoid differentiation d Wdr5 inhibition stabilizes p53 and activates p53 signaling d Transient Wdr5 inhibition stimulates ESC differentiation toward mesoderm fates via p53

Cited by 20 publications

References 60 publications

STRAP regulates alternative splicing fidelity during lineage commitment of mouse embryonic stem cells

STRAP regulates alternative splicing fidelity during lineage commitment of mouse embryonic stem cells

Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity

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

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