Cancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17

Srivastava, Yogesh; Tan, Daisylyn Senna; Malik, Vikas; Weng, Mingxi; Javed, Asif; Cojocaru, Vlad; Wu, Guangming; Veerapandian, Veeramohan; Cheung, Lydia W.T.; Jauch, Ralf

doi:10.1111/febs.15076

Cited by 11 publications

(8 citation statements)

References 107 publications

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“…The fact that modification of S131 results in an increase in activity that is independent of DNA binding suggests that reversible modification of the NANOG homeodomain may be used as a switch to regulate interactions between NANOG and partner proteins and to thereby modulate ESC self-renewal efficiency. Future work should address this issue and the alternative possibility that S131D affects protein stability as is the case for the SOX17 gain-of-function mutant SOX17 V118M [58].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal

et al. 2020

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The self-renewal efficiency of mouse embryonic stem cells (ESCs) is determined by the concentration of the transcription factor NANOG. While NANOG binds thousands of sites in chromatin, the regulatory systems that control DNA binding are poorly characterised. Here, we show that NANOG is phosphorylated by casein kinase I, and identify target residues. Phosphomimetic substitutions at phosphorylation sites within the homeodomain (S130 and S131) have site-specific functional effects. Phosphomimetic substitution of S130 abolishes DNA binding by NANOG and eliminates LIF-independent self-renewal. In contrast, phosphomimetic substitution of S131 enhances LIFindependent self-renewal, without influencing DNA binding. Modelling the DNA-homeodomain complex explains the disparate effects of these phosphomimetic substitutions. These results indicate how phosphorylation may influence NANOG homeodomain interactions that underpin ESC self-renewal.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal

et al. 2020

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“…The high mobility group (HMG) domains of Sox2 and Sox17 were expressed and purified as described in ( Ng et al. 2012 ; Srivastava et al. 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Directed Evolution of an Enhanced POU Reprogramming Factor for Cell Fate Engineering

Tan

Chen

Gao

et al. 2021

Molecular Biology and Evolution

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Transcription factor-driven cell fate engineering in pluripotency induction, transdifferentiation, and forward reprogramming require efficiency, speed, and maturity for widespread adoption and clinical translation. Here, we used Oct4, Sox2, Klf4, c-Myc driven pluripotency reprogramming to evaluate methods for enhancing and tailoring cell fate transitions, through directed evolution with iterative screening of pooled mutant libraries and phenotypic selection. We identified an artificially evolved and enhanced POU factor (ePOU) that substantially outperforms wild-type Oct4 in terms of reprogramming speed and efficiency. In contrast to Oct4, ePOU can induce pluripotency with Sox2 alone and in the absence of Sox2 in three factor - ePOU/Klf4/c-Myc cocktails. Biochemical assays combined with genome-wide analyses show that ePOU acquires a new preference to dimerize on palindromic DNA elements. Yet, the moderate capacity of Oct4 to function as a pioneer factor, its preference to bind octamer DNA and its capability to dimerize with Sox2 and Sox17 proteins are not changed in ePOU. Compared to Oct4, ePOU is thermodynamically stabilized and persists longer in reprogramming cells. In consequence, ePOU: (1) differentially activates several genes hitherto not implicated in reprogramming, (2) reveals an unappreciated role of thyrotropin-releasing hormone signaling, and (3) binds a distinct class of retrotransposons. Collectively, these features enabled ePOU to accelerate the establishment of the pluripotency network. This demonstrates that the phenotypic selection of novel factor variants from mammalian cells with desired properties is key to advancing cell fate conversions with artificially evolved biomolecules.

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“…The copyright holder for this this version posted December 2, 2022. ; https://doi.org/10.1101/2022.12.01.518778 doi: bioRxiv preprint 4 mutations in the transcription factor SOX17 can confer reprogramming capability to the normally incapable SOX17 (Srivastava et al, 2020).…”

Section: Somatic Cells Can Be Reprogrammed To Induced Pluripotent Ste...mentioning

confidence: 99%

Modulating the epigenetic state promotes the reprogramming of transformed cells to pluripotency in a line-specific manner

Zhuang

Babarinde

et al. 2022

Preprint

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Somatic cell reprogramming and oncogenic transformation share surprisingly similar features, yet transformed cells are highly resistant to reprogramming. There must be barriers that block transformed cells from reprogramming, but the nature of those barriers is unclear. In this study, we generated a systematic panel of transformed mouse embryonic fibroblasts (MEFs) using a variety of oncogenic transgenes, and discovered transformed cell lines that remain compatible with reprogramming when transfected with Oct4/Sox2/Klf4/Myc. By comparing the reprogramming-capable and incapable transformed lines we identified multiple stages of failure in the reprogramming process. Some transformed lines failed very early, whilst other lines seemed to progress through a normal-looking reprogramming process. Finally, we show that MEK inhibition overcomes one critical reprogramming barrier by indirectly suppressing a hyperactive epigenetic state in some of the transformed cells. This study reveals that the barriers underlying resistance to reprogramming vary between the different transformation methods.

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Cancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17

Cited by 11 publications

References 107 publications

Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal

Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal

Directed Evolution of an Enhanced POU Reprogramming Factor for Cell Fate Engineering

Modulating the epigenetic state promotes the reprogramming of transformed cells to pluripotency in a line-specific manner

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