scholarly journals Oct4-mediated inhibition of Lsd1 activity promotes the active and primed state of pluripotency enhancers

2019 ◽  
Author(s):  
Lama AlAbdi ◽  
Debapriya Saha ◽  
Ming He ◽  
Mohd Saleem Dar ◽  
Sagar M. Utturkar ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Dna Hypomethylation ◽  
Dependent Inhibition ◽  
Pluripotency Gene ◽  
Primed State ◽  
F9 Embryonal Carcinoma Cells

SummaryAn aberrant increase in pluripotency gene (PpG) expression due to enhancer reactivation could induce stemness and enhance tumorigenicity of cancer stem cells. Silencing of PpG enhancers (PpGe) during embryonic stem cell differentiation involves Lsd1–mediated H3K4me1 demethylation and DNA methylation. Here, we observed retention of H3K4me1 and DNA hypomethylation at PpGe associated with a partial repression of PpGs in F9 embryonal carcinoma cells (ECCs) post-differentiation. H3K4me1 demethylation in F9 ECCs could not be rescued by Lsd1 overexpression. Given our observation that H3K4me1 demethylation is accompanied by strong Oct4 repression in P19 ECCs, we tested if Oct4 interaction with Lsd1 affects its catalytic activity. Our data show a dose-dependent inhibition of Lsd1 activity by Oct4 and retention of H3K4me1 at PpGe in Oct4 overexpressing P19 ECCs. These data suggest that Lsd1-Oct4 interaction in cancer stem cells could establish a primed enhancer state that is susceptible to reactivation leading to aberrant PpG expression.

scholarly journals A Case of Identity: HOX Genes in Normal and Cancer Stem Cells

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 512 ◽  
Author(s):  
Smith ◽  
Zyoud ◽  
Allegrucci
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Cancer Stem Cells ◽  
Adult Stem Cells ◽  
Hox Genes ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Hox Gene

Stem cells are undifferentiated cells that have the unique ability to self-renew and differentiate into many different cell types. Their function is controlled by core gene networks whose misregulation can result in aberrant stem cell function and defects of regeneration or neoplasia. HOX genes are master regulators of cell identity and cell fate during embryonic development. They play a crucial role in embryonic stem cell differentiation into specific lineages and their expression is maintained in adult stem cells along differentiation hierarchies. Aberrant HOX gene expression is found in several cancers where they can function as either oncogenes by sustaining cell proliferation or tumor-suppressor genes by controlling cell differentiation. Emerging evidence shows that abnormal expression of HOX genes is involved in the transformation of adult stem cells into cancer stem cells. Cancer stem cells have been identified in most malignancies and proved to be responsible for cancer initiation, recurrence, and metastasis. In this review, we consider the role of HOX genes in normal and cancer stem cells and discuss how the modulation of HOX gene function could lead to the development of novel therapeutic strategies that target cancer stem cells to halt tumor initiation, progression, and resistance to treatment.

scholarly journals Induction of Cancerous Stem Cells during Embryonic Stem Cell Differentiation

2012 ◽  
Vol 287 (44) ◽  
pp. 36777-36791 ◽  
Author(s):  
Hiroaki Fujimori ◽  
Mima Shikanai ◽  
Hirobumi Teraoka ◽  
Mitsuko Masutani ◽  
Ken-ichi Yoshioka
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation

scholarly journals Regulated expression of the small nuclear ribonucleoprotein particle protein SmN in embryonic stem cell differentiation.

1990 ◽  
Vol 10 (12) ◽  
pp. 6817-6820 ◽  
Author(s):  
N G Sharpe ◽  
D G Williams ◽  
D S Latchman
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Lines ◽  
Embryonal Carcinoma ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Embryonal Carcinoma Cell ◽  
Small Nuclear Ribonucleoprotein ◽  
Nuclear Ribonucleoprotein

The SmN protein is a component of small nuclear ribonucleoprotein particles and is closely related to the ubiquitous SmB and B' splicing proteins. It is expressed in a limited range of tissues and cell types, including several undifferentiated embryonal carcinoma cell lines and undifferentiated embryonic stem cells. The protein declines to undetectable levels when embryonal carcinoma or embryonic stem cells are induced to differentiate, producing primitive endoderm or parietal endoderm or yielding embryonal bodies. This decline is due to a corresponding decrease in the level of the SmN mRNA. The potential role of SmN in the regulation of alternative splicing in embryonic cell lines and early embryos is discussed.

scholarly journals Increased intracellular pH is necessary for adult epithelial and embryonic stem cell differentiation

2016 ◽  
Vol 215 (3) ◽  
pp. 345-355 ◽  
Author(s):  
Bryne Ulmschneider ◽  
Bree K. Grillo-Hill ◽  
Marimar Benitez ◽  
Dinara R. Azimova ◽  
Diane L. Barber ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Intracellular Ph ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Follicle Cells ◽  
Stalk Cell ◽  
Embryonic Stem Cell Differentiation

Despite extensive knowledge about the transcriptional regulation of stem cell differentiation, less is known about the role of dynamic cytosolic cues. We report that an increase in intracellular pH (pHi) is necessary for the efficient differentiation of Drosophila adult follicle stem cells (FSCs) and mouse embryonic stem cells (mESCs). We show that pHi increases with differentiation from FSCs to prefollicle cells (pFCs) and follicle cells. Loss of the Drosophila Na+–H+ exchanger DNhe2 lowers pHi in differentiating cells, impairs pFC differentiation, disrupts germarium morphology, and decreases fecundity. In contrast, increasing pHi promotes excess pFC cell differentiation toward a polar/stalk cell fate through suppressing Hedgehog pathway activity. Increased pHi also occurs with mESC differentiation and, when prevented, attenuates spontaneous differentiation of naive cells, as determined by expression of microRNA clusters and stage-specific markers. Our findings reveal a previously unrecognized role of pHi dynamics for the differentiation of two distinct types of stem cell lineages, which opens new directions for understanding conserved regulatory mechanisms.

scholarly journals Downregulation of E-cadherin in pluripotent stem cells triggers partial EMT

2020 ◽  
Author(s):  
C. Aban ◽  
A. Lombardi ◽  
G. Neiman ◽  
M.C. Biani ◽  
A. La Greca ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Connexin 43 ◽  
Cancer Metastasis ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Mesenchymal Transition ◽  
E Cadherin

Epithelial to mesenchymal transition (EMT) is a critical cellular process that has been well characterized during embryonic development and cancer metastasis and it also is implicated in several physiological and pathological events including embryonic stem cell differentiation. During early stages of differentiation, human embryonic stem cells pass through EMT where deeper morphological, molecular and biochemical changes occur. Though initially considered as a decision between two states, EMT process is now regarded as a fluid transition where cells exist on a spectrum of intermediate states. In this work, using a CRISPR interference system in human embryonic stem cells, we describe a molecular characterization of the effects of downregulation of E-cadherin, one of the main initiation events of EMT, as a unique start signal. Our results suggest that the decrease and delocalization of E-cadherin causes an incomplete EMT where cells retain their undifferentiated state while expressing several characteristics of a mesenchymal-like pheno-type. Namely, we found that E-cadherin downregulation induces SNAI1 and SNAI2 upregulation, promotes MALAT1 and LINC-ROR downregulation, modulates the expression of tight junction occludin 1 and gap junction connexin 43, increases human embryonic stem cells migratory capacity and delocalize b-catenin. Altogether, we believe our results provide a useful tool to model the molecular events of an unstable intermediate state and further identify multiple layers of molecular changes that occur during partial EMT.

212 Increased expression of YAP/TAZ encourages outgrowth establishment and three-dimensional colony formation and boosts plasticity of parthenogenetic stem cells

2020 ◽  
Vol 32 (2) ◽  
pp. 234
Author(s):  
S. Arcuri ◽  
G. Pennarossa ◽  
F. Gandolfi ◽  
T. Brevini
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Direct Interaction ◽  
High Plasticity ◽  
Dna Hypomethylation ◽  
Regulatory Pathways ◽  
Pluripotency Gene ◽  
The Cost

Cell proliferation, apoptosis, and differentiation are essential processes from the early phases of embryogenesis to adult tissue formation and maintenance. These mechanisms also play a key role in embryonic stem cells (ESCs), which are able to proliferate maintaining pluripotency and, at the same time, give rise to all populations belonging to the three germ layers in response to specific stimuli. ESCs are, therefore, considered a well-established invitro model to study the complexity of these processes. We previously generated porcine and human diploid parthenogenetic embryonic stem cells (ParthESC) that showed many features and regulatory pathways common to biparental ESCs. However, we observed that monoparental cells demonstrated a greater ability to form outgrowths and generate stable three-dimensional (3D) spheroid colonies, which are distinctive signs of high plasticity (Brevini et al. 2010 STCR 6; https://doi.org/10.1007/s12015-010-9153-2). In the present study, we compared porcine and human biparental ESCs and ParthESC. Pluripotency gene expression was analysed and ELISA tests for global DNA methylation and total YAP levels were performed. Our results showed that ParthESCs showed significantly higher expression levels of YAP and TAZ than biparental ESCs. In contrast, the analysis of the upstream genes involved in the Hippo signalling pathway revealed no differences. We demonstrated that YAP remains in a dephosphorylated form, encouraging its nuclear compartmentalization and direct interaction with the nuclear transcription factors TEADs and SMADs, that are also upregulated and maintain pluripotency, repressing differentiation processes (Beyer et al. 2013 Cell Rep. 5, 1611-1624; https://doi.org/10.1016/j.celrep.2013.11.021). These complex regulatory interactions accompanied the overexpression of the pluripotency-related genes OCT4, NANOG, REX1, SOX2, UTF1, and TERT. In parallel, we observed a decrease of DNMT3 and DNMT4 activity that resulted in a global DNA hypomethylation and a chromatin high-permissive state. Altogether, our results demonstrate a significant upregulation of YAP/TAZ activity in monoparental cell lines. This may account for their greater ability to form outgrowths and generate 3D spheroid colonies and increased plasticity compared with biparental counterparts. It is interesting to note that YAP mRNA is supplied and expressed by the oocyte and is maternally inherited (Yu et al. 2016 Cell Res. 26, 275-287; https://doi.org/10.1038/cr.2016.20). Although further clarifications are needed, we hypothesise that its higher expression in ParthESC may be related to the strictly maternal origin of these cells. This study was supported by the Carraresi Foundation. Authors are members of the COST Actions CA16119.

scholarly journals Cell surface mechanics gate stem cell differentiation

2019 ◽  
Author(s):  
Martin Bergert ◽  
Sergio Lembo ◽  
Danica Milovanović ◽  
Mandy Börmel ◽  
Pierre Neveu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Plasma Membrane ◽  
Cell Differentiation ◽  
Cell Surface ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Membrane Mechanics ◽  
Actin Cortex ◽  
Primed State ◽  
Surface Mechanics

AbstractCell differentiation typically occurs with concomitant shape transitions to enable specialized functions. To adopt a different shape, cells need to change the mechanical properties of their surface. However, whether conversely cell surface mechanics control the process of differentiation has been relatively unexplored. Here, we show that membrane mechanics gate the exit from naïve pluripotency of mouse embryonic stem cells. By measuring membrane tension during differentiation, we find that naïve stem cells release their plasma membrane from the underlying actin cortex when transitioning to a primed state. By mechanically tethering the plasma membrane to the cortex with a synthetic signalling-inert linker, we demonstrate that preventing this detachment forces stem cells to retain their naïve pluripotent state. We thus identify a decrease in membrane-to-cortex attachment as a new cell-intrinsic mechanism that is essential for stem cells to exit pluripotency.

Regulated expression of the small nuclear ribonucleoprotein particle protein SmN in embryonic stem cell differentiation

1990 ◽  
Vol 10 (12) ◽  
pp. 6817-6820
Author(s):  
N G Sharpe ◽  
D G Williams ◽  
D S Latchman
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Lines ◽  
Embryonal Carcinoma ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Embryonal Carcinoma Cell ◽  
Small Nuclear Ribonucleoprotein ◽  
Nuclear Ribonucleoprotein

The SmN protein is a component of small nuclear ribonucleoprotein particles and is closely related to the ubiquitous SmB and B' splicing proteins. It is expressed in a limited range of tissues and cell types, including several undifferentiated embryonal carcinoma cell lines and undifferentiated embryonic stem cells. The protein declines to undetectable levels when embryonal carcinoma or embryonic stem cells are induced to differentiate, producing primitive endoderm or parietal endoderm or yielding embryonal bodies. This decline is due to a corresponding decrease in the level of the SmN mRNA. The potential role of SmN in the regulation of alternative splicing in embryonic cell lines and early embryos is discussed.

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