Brief Report: Cell Cycle Dynamics of Human Pluripotent Stem Cells Primed for Differentiation

Shcherbina, Anna; Li, Jingling; Narayanan, C. H.; Greenleaf, William J.; Kundaje, Anshul; Chetty, Sundari

doi:10.1002/stem.3041

Cited by 8 publications

(5 citation statements)

References 38 publications

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“…RBBP4 was originally identified based on its interaction with the Rb tumor suppressor protein ( Qian et al., 1993 ), which is essential for the maintenance of self-renewal and pluripotency in human ESCs ( Chetty et al., 2013 ; Conklin et al., 2012 ; Conklin and Sage, 2009 ; Li et al., 2018b ). The results of these studies in human ESCs together with our finding consolidate the notion that cell-cycle machinery and the maintenance of pluripotency are intricately connected to safeguard ESC identity ( Pauklin and Vallier, 2013 ; Ruiz et al., 2011 ; Shcherbina et al., 2019 ). Interestingly, prevalent overexpression of Rbbp4 has been implicated in a variety of malignancies ( Li et al., 2018a ), suggesting that induction of carcinoma cell differentiation by directly targeting Rbbp4 might be a promising therapeutic approach for tumor treatment.…”

Section: Discussionsupporting

confidence: 81%

Rbbp4 Suppresses Premature Differentiation of Embryonic Stem Cells

Huang

Liu

et al. 2021

Stem Cell Reports

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Summary Polycomb group (PcG) proteins exist in distinct multi-protein complexes and play a central role in silencing developmental genes, yet the underlying mechanisms remain elusive. Here, we show that deficiency of retinoblastoma binding protein 4 (RBBP4), a component of the Polycomb repressive complex 2 (PRC2), in embryonic stem cells (ESCs) leads to spontaneous differentiation into mesendodermal lineages. We further show that Rbbp4 and core PRC2 share an important number of common genomic targets, encoding regulators involved in early germ layer specification. Moreover, we find that Rbbp4 is absolutely essential for genomic targeting of PRC2 to a subset of developmental genes. Interestingly, we demonstrate that Rbbp4 is necessary for sustaining the expression of Oct4 and Sox2 and that the forced co-expression of Oct4 and Sox2 fully rescues the pluripotency of Rbbp4 -null ESCs. Therefore, our study indicates that Rbbp4 links maintenance of the pluripotency regulatory network with repression of mesendoderm lineages.

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Section: Discussionsupporting

confidence: 81%

Rbbp4 Suppresses Premature Differentiation of Embryonic Stem Cells

Huang

Liu

et al. 2021

Stem Cell Reports

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“…Particularly, the cell-cycle inhibitor CYT triggered cell-cycle arrest and 2C gene activation independent of the ATR-CHK1-pathway and the p53 pathway. Particularly, we have noted that the fluorescence ubiquitination cell-cycle indicator (FUCCI) system has been widely used in cell-cycle studies, as it enables real-time monitoring of different phases of the cell cycle in living cells ( Chetty et al., 2013 ; Sakaue-Sawano et al., 2017 ; Shcherbina et al., 2019 ), which is a powerful tool for elaborating the duration of 2C emergence and exit at different cell-cycle phases in our next study.…”

Section: Discussionmentioning

confidence: 96%

Cell cycle heterogeneity directs spontaneous 2C state entry and exit in mouse embryonic stem cells

Zhu¹,

Cheng²,

Chen³

et al. 2021

Stem Cell Reports

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Mouse embryonic stem cells (ESCs) show cell-to-cell heterogeneity. A small number of two-cell-like cells (2CLCs) marked by endogenous retrovirus activation emerge spontaneously. The 2CLCs are unstable and they are prone to transiting back to the pluripotent state without extrinsic stimulus. To understand how this bidirectional transition takes place, we performed single-cell RNA sequencing on isolated 2CLCs that underwent 2C-like state exit and re-entry, and revealed a step-by-step transitional process between 2C-like and pluripotent states. Mechanistically, we found that cell cycle played an important role in mediating these transitions by regulating assembly of the nucleolus and peri-nucleolar heterochromatin to influence 2C gene Dux expression. Collectively, our findings provide a roadmap of the 2C-like state entry and exit in ESCs and also a causal role of the cell cycle in promoting these transitions.

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“…Conversely, knock-down of Akt1 leads to loss of mESC self-renewal [65,66]. Pharmacological PI3K inhibition in hPSCs has also been linked to increased differentiation [67][68][69][70][71], yet the evidence is mainly based on the use of the pan-PI3K inhibitors, LY294002 and wortmannin, which are known to be promiscuous towards multiple other kinasesincluding mTORat the applied concentrations [72][73][74][75][76]. The use of these inhibitors is strongly discouraged by experts in the PI3K signalling field [4].…”

Section: Pi3k-induced Stemness In Mouse and Human Pscsmentioning

confidence: 99%

PI3K in stemness regulation: from development to cancer

Madsen

2020

Biochemical Society Transactions

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The PI3K/AKT pathway is a key target in oncology where most efforts are focussed on phenotypes such as cell proliferation and survival. Comparatively, little attention has been paid to PI3K in stemness regulation, despite the emerging link between acquisition of stem cell-like features and therapeutic failure in cancer. The aim of this review is to summarise current known and unknowns of PI3K-dependent stemness regulation, by integrating knowledge from the fields of developmental, signalling and cancer biology. Particular attention is given to the role of the PI3K pathway in pluripotent stem cells (PSCs) and the emerging parallels to dedifferentiated cancer cells with stem cell-like features. Compelling evidence suggests that PI3K/AKT signalling forms part of a ‘core molecular stemness programme’ in both mouse and human PSCs. In cancer, the oncogenic PIK3CAH1047R variant causes constitutive activation of the PI3K pathway and has recently been linked to increased stemness in a dose-dependent manner, similar to observations in mouse PSCs with heterozygous versus homozygous Pten loss. There is also evidence that the stemness phenotype may become ‘locked’ and thus independent of the original PI3K activation, posing limitations for the success of PI3K monotherapy in cancer. Ongoing therapeutic developments for PI3K-associated cancers may therefore benefit from a better understanding of the pathway's two-layered and highly context-dependent regulation of cell growth versus stemness.

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Brief Report: Cell Cycle Dynamics of Human Pluripotent Stem Cells Primed for Differentiation

Cited by 8 publications

References 38 publications

Rbbp4 Suppresses Premature Differentiation of Embryonic Stem Cells

Rbbp4 Suppresses Premature Differentiation of Embryonic Stem Cells

Cell cycle heterogeneity directs spontaneous 2C state entry and exit in mouse embryonic stem cells

PI3K in stemness regulation: from development to cancer

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