DO MRPS18-2 AND RB PROTEINS COOPERATE TO CONTROL CELL STEMNESS AND DIFFERENTIATION, PREVENTING CANCER DEVELOPMENT?

In childhood tumors, including retinoblastoma, osteosarcoma, and neuroblastoma, the RB-E2F1 pathway is inactivated, as a rule. These tumors arise from precursor cells that fail to undergo the terminal differentiation. Noteworthy, the RB1-encoded protein (RB) does not control the cell cycle in embryonic stem cells. It has not been yet well understood how RB controls cell stemness and differentiation. The question arises why “inactive” RB is required for the survival and stemness of cells? Recently, we have found that overexpression of the RB-binding protein MRPS18-2 (S18-2) in primary fibroblasts leads to their immortalization, which is accompanied by the induction of embryonic stem cell markers and, eventually, malignant transformation. We suggest that cell stemness may be associated with high expression levels of both proteins, RB and S18-2. There must be a strict regulation of the expression levels of S18-2 and RB during embryogenesis. Disturbances in the expression of these proteins would lead to the abnormalities in development. We think that the S18-2 protein, together with the RB, plays a crucial role in the control on cell stemness and differentiation. We hope to uncover the new mechanisms of the cell fate determination. The S18-2 may serve as a new target for anticancer medicines, which will help to improve human health.

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The expression of mesenchymal and embryonic stem cell markers by human limbal Stromal cells

PsycEXTRA Dataset ◽

10.1037/e602332011-001 ◽

2011 ◽

Author(s):

Moon Nian Lim ◽

Umapathy Thiageswari ◽

Othman Ainoon ◽

P. J. N. Baharuddin ◽

R. A. Jamal ◽

...

Keyword(s):

Stem Cell ◽

Embryonic Stem Cell ◽

Stromal Cells ◽

Embryonic Stem ◽

Stem Cell Markers ◽

Cell Markers ◽

Embryonic Stem Cell Markers

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Nicotinamide promotes pancreatic differentiation through the dual inhibition of CK1 and ROCK kinases in human embryonic stem cells

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02426-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yumeng Zhang ◽

Jiaqi Xu ◽

Zhili Ren ◽

Ya Meng ◽

Weiwei Liu ◽

...

Keyword(s):

Stem Cells ◽

Cell Fate ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Cell Fate Determination ◽

Rna Seq ◽

Pancreatic Cell ◽

Pancreatic Progenitor ◽

Pancreatic Progenitors ◽

Rock Inhibition

Abstract Background Vitamin B3 (nicotinamide) plays important roles in metabolism as well as in SIRT and PARP pathways. It is also recently reported as a novel kinase inhibitor with multiple targets. Nicotinamide promotes pancreatic cell differentiation from human embryonic stem cells (hESCs). However, its molecular mechanism is still unclear. In order to understand the molecular mechanism involved in pancreatic cell fate determination, we analyzed the downstream pathways of nicotinamide in the derivation of NKX6.1+ pancreatic progenitors from hESCs. Methods We applied downstream modulators of nicotinamide during the induction from posterior foregut to pancreatic progenitors, including niacin, PARP inhibitor, SIRT inhibitor, CK1 inhibitor and ROCK inhibitor. The impact of those treatments was evaluated by quantitative real-time PCR, flow cytometry and immunostaining of pancreatic markers. Furthermore, CK1 isoforms were knocked down to validate CK1 function in the induction of pancreatic progenitors. Finally, RNA-seq was used to demonstrate pancreatic induction on the transcriptomic level. Results First, we demonstrated that nicotinamide promoted pancreatic progenitor differentiation in chemically defined conditions, but it did not act through either niacin-associated metabolism or the inhibition of PARP and SIRT pathways. In contrast, nicotinamide modulated differentiation through CK1 and ROCK inhibition. We demonstrated that CK1 inhibitors promoted the generation of PDX1/NKX6.1 double-positive pancreatic progenitor cells. shRNA knockdown revealed that the inhibition of CK1α and CK1ε promoted pancreatic progenitor differentiation. We then showed that nicotinamide also improved pancreatic progenitor differentiation through ROCK inhibition. Finally, RNA-seq data showed that CK1 and ROCK inhibition led to pancreatic gene expression, similar to nicotinamide treatment. Conclusions In this report, we revealed that nicotinamide promotes generation of pancreatic progenitors from hESCs through CK1 and ROCK inhibition. Furthermore, we discovered the novel role of CK1 in pancreatic cell fate determination.

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The methyl binding domain 3/nucleosome remodelling and deacetylase complex regulates neural cell fate determination and terminal differentiation in the cerebral cortex

Neural Development ◽

10.1186/s13064-015-0040-z ◽

2015 ◽

Vol 10 (1) ◽

Cited By ~ 27

Author(s):

Erin Knock ◽

João Pereira ◽

Patrick D Lombard ◽

Andrew Dimond ◽

Donna Leaford ◽

...

Keyword(s):

Cerebral Cortex ◽

Cell Fate ◽

Terminal Differentiation ◽

Neural Cell ◽

Binding Domain ◽

Cell Fate Determination ◽

Fate Determination ◽

Domain 3 ◽

Neural Cell Fate

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POGZ controls embryonic stem cell self-renewal and pluripotency by association with esBAF and HP1

10.1101/2021.02.07.430173 ◽

2021 ◽

Author(s):

Xiaoyun Sun ◽

Linxi Cheng ◽

Yuhua Sun

Keyword(s):

Cell Fate ◽

Neurodevelopmental Disorders ◽

Embryonic Stem ◽

Autism Spectrum ◽

Specific Gene ◽

Open Chromatin ◽

Cell Fate Determination ◽

Chromatin Remodeler ◽

Self Renewal ◽

Fate Determination

AbstractPOGZ, which encodes a multi-domain transcription factor, has been found frequently mutated in neurodevelopmental disorders, particularly autism spectrum disorder (ASD) and intellectual disability (ID). However, little is known about its function in ESC self-renewal and pluripotency, cell fate determination as well as in transcriptional regulation. Here, using embryonic stem cells (ESCs) as model, we show that POGZ plays key roles in the maintenance of ESC and cell fate determination by association with the SWI-SNW chromatin remodeler complex and heterochromatin protein 1 (HP1) proteins. POGZ is essential for the maintenance of ESC undifferentiated state, and loss of POGZ leads to ESC differentiation, likely by up-regulation of primitive endoderm and mesoderm lineage genes and by down-regulation of pluripotency-related genes. Mechanistically, POGZ may control ESC-specific gene expression by association with chromatin remodeler complex esBAF and HP1s, and they can form a PBH triplex. POGZ functions primarily to maintain an open chromatin, as loss of POGZ leads to a reduced chromatin accessibility. Regulation of chromatin under control of POGZ depends on esBAF complex. POGZ is extensively co-localized with OCT4/NANOG genome wide. Taken together, we propose that POGZ is a pluripotency-associated factor, and its absence in ESCs causes failure to maintain a proper ESC-specific chromatin state and transcriptional circuitry of pluripotency, which eventually leads to ESC self-renewal and pluripotency defects. Our work provides important insights into the role of POGZ in ESC self-renewal and pluripotency as well as regulation of transcription, which will be useful for understanding the etiology of neurodevelopmental disorders by POGZ mutation.

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LncRNA Platr22 promotes super-enhancer activity and stem cell pluripotency

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjaa056 ◽

2020 ◽

Author(s):

Pixi Yan ◽

J Yuyang Lu ◽

Jing Niu ◽

Juntao Gao ◽

Michael Q Zhang ◽

...

Keyword(s):

Cell Fate ◽

Noncoding Rna ◽

Embryonic Stem ◽

Cell Fate Determination ◽

Enhancer Activity ◽

Lncrna Gene ◽

Fate Determination ◽

Super Enhancer ◽

Stem Cell Pluripotency ◽

Active Transcription

Abstract Super-enhancers (SEs) comprise large clusters of enhancers, which are co-occupied by multiple lineage-specific and master transcription factors, and play pivotal roles in regulating gene expression and cell fate determination. However, it is still largely unknown whether and how SEs are regulated by the non-coding portion of the genome. Here, through genome-wide analysis, we found that long noncoding RNA (lncRNA) genes preferentially lie next to SEs. In mouse embryonic stem cells (mESCs), depletion of SE-associated lncRNA transcripts dysregulated the activity of their nearby SEs. Specifically, we revealed a critical regulatory role of the lncRNA gene Platr22 in modulating the activity of a nearby SE and the expression of the nearby pluripotency regulator ZFP281. Through these regulatory events, Platr22 contributes to pluripotency maintenance and proper differentiation of mESCs. Mechanistically, Platr22 transcripts coat chromatin near the SE region and interact with DDX5 and hnRNP-L. DDX5 further recruits p300 and other factors related to active transcription. We propose that these factors assemble into a transcription hub, thus promoting an open and active epigenetic chromatin state. Our study highlights an unanticipated role for a class of lncRNAs in epigenetically controlling the activity and vulnerability to perturbation of nearby SEs for cell fate determination.

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Expression of embryonic stem cell markers in pyogenic granuloma

Journal of Cutaneous Pathology ◽

10.1111/cup.12786 ◽

2016 ◽

Vol 43 (12) ◽

pp. 1096-1101 ◽

Cited By ~ 6

Author(s):

Max G. Blackwell ◽

Tinte Itinteang ◽

Alice M. Chibnall ◽

Paul F. Davis ◽

Swee T. Tan

Keyword(s):

Stem Cell ◽

Embryonic Stem Cell ◽

Embryonic Stem ◽

Pyogenic Granuloma ◽

Stem Cell Markers ◽

Cell Markers ◽

Embryonic Stem Cell Markers

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Chromatin Assembly Factor 1 (CAF-1) facilitates the establishment of facultative heterochromatin during pluripotency exit

Nucleic Acids Research ◽

10.1093/nar/gkz858 ◽

2019 ◽

Vol 47 (21) ◽

pp. 11114-11131 ◽

Cited By ~ 10

Author(s):

Liang Cheng ◽

Xu Zhang ◽

Yan Wang ◽

Haiyun Gan ◽

Xiaowei Xu ◽

...

Keyword(s):

Cell Fate ◽

Embryonic Stem ◽

Chromatin Assembly ◽

Nuclear Antigen ◽

Gene Promoters ◽

Cell Fate Determination ◽

Nucleosome Assembly ◽

Fate Determination ◽

Chromatin Assembly Factor ◽

Assembly Factor

Abstract Establishment and subsequent maintenance of distinct chromatin domains during embryonic stem cell (ESC) differentiation are crucial for lineage specification and cell fate determination. Here we show that the histone chaperone Chromatin Assembly Factor 1 (CAF-1), which is recruited to DNA replication forks through its interaction with proliferating cell nuclear antigen (PCNA) for nucleosome assembly, participates in the establishment of H3K27me3-mediated silencing during differentiation. Deletion of CAF-1 p150 subunit impairs the silencing of many genes including Oct4, Sox2 and Nanog as well as the establishment of H3K27me3 at these gene promoters during ESC differentiation. Mutations of PCNA residues involved in recruiting CAF-1 to the chromatin also result in defects in differentiation in vitro and impair early embryonic development as p150 deletion. Together, these results reveal that the CAF-1-PCNA nucleosome assembly pathway plays an important role in the establishment of H3K27me3-mediated silencing during cell fate determination.

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