Slc25a36 modulates pluripotency of mouse embryonic stem cells by regulating mitochondrial function and glutathione level

2019 ◽  
Vol 476 (11) ◽  
pp. 1585-1604 ◽  
Author(s):  
Yanli Xin ◽  
Yanliang Wang ◽  
Liang Zhong ◽  
Bingbo Shi ◽  
Hui Liang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Mitochondrial Dysfunction ◽  
Cell Fate ◽  
Mitochondrial Function ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Glutathione Metabolism ◽  
Pluripotency Maintenance

Abstract Mitochondria play a central role in the maintenance of the naive state of embryonic stem cells. Many details of the mechanism remain to be fully elucidated. Solute carrier family 25 member 36 (Slc25a36) might regulate mitochondrial function through transporting pyrimidine nucleotides for mtDNA/RNA synthesis. Its physical role in this process remains unknown; however, Slc25a36 was recently found to be highly expressed in naive mouse embryonic stem cells (mESCs). Here, the function of Slc25a36 was characterized as a maintenance factor of mESCs pluripotency. Slc25a36 deficiency (via knockdown) has been demonstrated to result in mitochondrial dysfunction, which induces the differentiation of mESCs. The expression of key pluripotency markers (Pou5f1, Sox2, Nanog, and Utf1) decreased, while that of key TE genes (Cdx2, Gata3, and Hand1) increased. Cdx2-positive cells emerged in Slc25a36-deficient colonies under trophoblast stem cell culture conditions. As a result of Slc25a36 deficiency, mtDNA of knockdown cells declined, leading to impaired mitochondria with swollen morphology, decreased mitochondrial membrane potential, and low numbers. The key transcription regulators of mitochondrial biogenesis also decreased. These results indicate that mitochondrial dysfunction leads to an inability to support the pluripotency maintenance. Moreover, down-regulated glutathione metabolism and up-regulated focal adhesion reinforced and stabilized the process of differentiation by separately enhancing OCT4 degradation and promoting cell spread. This study improves the understanding of the function of Slc25a36, as well as the relationship of mitochondrial function with naive pluripotency maintenance and stem cell fate decision.

scholarly journals Histone Acetyltransferase KAT2A Stabilises Pluripotency with Control of Transcriptional Heterogeneity

2018 ◽  
Author(s):  
Naomi Moris ◽  
Shlomit Edri ◽  
Denis Seyres ◽  
Rashmi Kulkarni ◽  
Ana Filipa Domingues ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Environmental Changes ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Histone Acetyl Transferase ◽  
Unicellular Organisms

ABSTRACTCell fate transitions in mammalian stem cell systems have often been associated with transcriptional heterogeneity, however existing data have failed to establish a functional or mechanistic link between the two phenomena. Experiments in unicellular organisms support the notion that transcriptional heterogeneity can be used to facilitate adaptability to environmental changes and have identified conserved chromatin-associated factors that modulate levels of transcriptional noise. Herein, we show destabilisation of pluripotency-associated gene regulatory networks through increased transcriptional heterogeneity of mouse embryonic stem cells in which paradigmatic histone acetyl-transferase, and candidate noise modulator, Kat2a (yeast orthologue Gcn5) has been inhibited. Functionally, network destabilisation associates with reduced pluripotency and accelerated mesendodermal differentiation, with increased probability of transitions into lineage commitment. Thus, we functionally link transcriptional heterogeneity to cell fate transitions through manipulation of the histone acetylation landscape of mouse embryonic stem cells and establish a general paradigm that could be exploited in other normal and malignant stem cell fate transitions.

scholarly journals Distinct SoxB1 networks are required for naïve and primed pluripotency

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Andrea Corsinotti ◽  
Frederick CK Wong ◽  
Tülin Tatar ◽  
Iwona Szczerbinska ◽  
Florian Halbritter ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Neural Differentiation ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Self Renewal ◽  
Cell Fate Decisions ◽  
Pluripotent State

Deletion of Sox2 from mouse embryonic stem cells (ESCs) causes trophectodermal differentiation. While this can be prevented by enforced expression of the related SOXB1 proteins, SOX1 or SOX3, the roles of SOXB1 proteins in epiblast stem cell (EpiSC) pluripotency are unknown. Here, we show that Sox2 can be deleted from EpiSCs with impunity. This is due to a shift in the balance of SoxB1 expression in EpiSCs, which have decreased Sox2 and increased Sox3 compared to ESCs. Consistent with functional redundancy, Sox3 can also be deleted from EpiSCs without eliminating self-renewal. However, deletion of both Sox2 and Sox3 prevents self-renewal. The overall SOXB1 levels in ESCs affect differentiation choices: neural differentiation of Sox2 heterozygous ESCs is compromised, while increased SOXB1 levels divert the ESC to EpiSC transition towards neural differentiation. Therefore, optimal SOXB1 levels are critical for each pluripotent state and for cell fate decisions during exit from naïve pluripotency.

scholarly journals Cancer stem cell induction from mouse embryonic stem cells

2019 ◽  
Author(s):  
Akimasa Seno ◽  
Chikae Murakami ◽  
Bishoy El‑Aarag ◽  
Yoshiaki Iwasaki ◽  
Toshiaki Ohara ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Cancer Stem Cell ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Cell Induction

scholarly journals Identification of Novel miRNAs in Mouse Embryonic Stem Cells, Embryonic Fibroblasts, and Reprogrammed Pluripotent Cells

2019 ◽  
Author(s):  
Botao Zhao ◽  
Chunsun Fan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
De Novo ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Mouse Embryonic Stem Cells ◽  
Pluripotent Cells ◽  
Embryonic Fibroblasts ◽  
Species Specific

AbstractMicroRNAs (miRNAs) are a class of non-coding small RNAs that function in almost every known cellular activity. MiRNAs play an important role in gene regulation that controls embryonic stem cell (ESC) pluripotency and differentiation, as well as induced pluripotent stem cell (iPSC) reprogramming. In this study, we identified nine novel miRNAs by mining the deep sequencing dataset from mouse embryonic stem cells, mouse embryonic fibroblasts (MEF) and three kinds of reprogrammed pluripotent cells. Most of them are non-conserved but species-specific and cell-specific miRNAs. Eight miRNAs are derived from gene introns, including a “mirtron” miRNA, miR-novel-41. We also showed that miR-novel-27 is a mouse-specific miRNA and the 5′ arm of its precursor hairpin, embedding the mature miR-novel-27, uniquely exists in mouse species but not in any other Placentalia animals. Notably, the 5′ arm of the pre-miR-novel-27 hairpin shows nearly perfect palindrome to the 3′ arm suggesting that it was generated by inverted duplication of the 3′ arm. By this mechanism, the pre-miR-novel-27 hairpin was de novo gained in the mouse genome. This is a new type of de novo miRNA emergence mechanism in animals, which we called “inverted local half hairpin duplication” here. In addition, very limited nucleotide mutants accumulated on the newly emerged 5′ arm since its birth suggesting an especially young evolutionary history of the miR-novel-27 gene.

scholarly journals Assessment of Stem Cell Markers During Long-Term Culture of Mouse Embryonic Stem Cells

2004 ◽  
Vol 44 (1/2) ◽  
pp. 77-91 ◽  
Author(s):  
A. Berrill ◽  
H.L. Tan ◽  
S.C. Wuang ◽  
W.J. Fong ◽  
Andre B.H. Choo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Long Term Culture
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