The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
Ian Chambers - One of the best experts on this subject based on the ideXlab platform.
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Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self-renewal.
FEBS letters, 2020Co-Authors: Nicholas P. Mullin, Joby Varghese, Douglas Colby, Julia M. Richardson, Greg M. Findlay, Ian ChambersAbstract: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 LIF-independent self-renewal, without influencing DNA binding. Modeling 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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TET1 Interacts Directly with NANOG via Independent Domains Containing Hydrophobic and Aromatic Residues
Journal of molecular biology, 2020Co-Authors: Raphaël Pantier, Nicholas P. Mullin, Elisa Hall-ponsele, Ian ChambersAbstract:The DNA demethylase TET1 is highly expressed in embryonic stem cells and is important both for lineage commitment, and reprogramming to naive pluripotency. TET1 interacts with the pluripotency Transcription Factor NANOG which may contribute to its biological activity in pluripotent cells. However, how TET1 interacts with other proteins is largely unknown. Here, we characterise the physical interaction between TET1 and NANOG using embryonic stem cells and bacterial expression systems. TET1 and NANOG interact through multiple binding sites that act independently. Critically, mutating conserved hydrophobic and aromatic residues within TET1 and NANOG abolishes the interaction. On chromatin, NANOG is predominantly localised at ESC enhancers. While TET1 binds to CpG dinucleotides in promoters using its CXXC domain, TET1 also binds to enhancers, though the mechanism involved is unknown. Comparative ChIP-seq analysis identifies genomic loci bound by both TET1 and NANOG, that correspond predominantly to pluripotency enhancers. Importantly, around half of NANOG Transcriptional target genes are associated with TET1-NANOG co-bound sites. These results indicate a mechanism by which TET1 protein may be targeted to specific sites of action at enhancers by direct interaction with a Transcription Factor.
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Endogenous epitope-tagging of Tet1, Tet2 and Tet3 identifies TET2 as a naïve pluripotency marker
Life science alliance, 2019Co-Authors: Raphaël Pantier, Douglas Colby, Tülin Tatar, Ian ChambersAbstract:Tet1, Tet2, and Tet3 encode DNA demethylases that play critical roles during stem cell differentiation and reprogramming to pluripotency. Although all three genes are transcribed in pluripotent cells, little is known about the expression of the corresponding proteins. Here, we tagged all the endogenous Tet family alleles using CRISPR/Cas9, and characterised TET protein expression in distinct pluripotent cell culture conditions. Whereas TET1 is abundantly expressed in both naive and primed pluripotent cells, TET2 expression is restricted to the naive state. Moreover, TET2 is expressed heterogeneously in embryonic stem cells (ESCs) cultured in serum/leukemia inhibitory Factor, with expression correlating with naive pluripotency markers. FACS-sorting of ESCs carrying a Tet2Flag-IRES-EGFP reporter demonstrated that TET2-negative cells have lost the ability to form undifferentiated ESC colonies. We further show that TET2 binds to the Transcription Factor NANOG. We hypothesize that TET2 and NANOG co-localise on chromatin to regulate enhancers associated with naive pluripotency genes.
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NANOG safeguards pluripotency and mediates germline development
Nature, 2007Co-Authors: Ian Chambers, Douglas Colby, José C.r. Silva, Jennifer Nichols, Bianca Nijmeijer, Morag Robertson, Jan Vrana, Ken JonesAbstract:In 2003 the Transcription Factor NANOG was identified as a key contributor to the property that makes embryonic stem cells unique: pluripotency. NANOG, named after Tir nan Og, the 'land of the forever-young' of Celtic myth, was thought to be required for stem cells to multiply while retaining the potential to differentiate. New work in mouse embryonic stem cells suggests a rather different picture. In fact NANOG is not essential for maintaining pluripotency; its levels fluctuate, but NANOG appears to stabilize the pluripotent state by resisting or reversing alternative states of gene expression. The Transcription Factor NANOG is considered a hallmark of pluripotent cells in vivo and in vitro, and loss of NANOG an early marker of differentiation. This is now revised by the demonstration that NANOG is not essential for maintaining pluripotency, but acts in stabilizing the pluripotent state. NANOG is a divergent homeodomain protein found in mammalian pluripotent cells and developing germ cells1,2. Deletion of NANOG causes early embryonic lethality2, whereas constitutive expression enables autonomous self-renewal of embryonic stem cells1. NANOG is accordingly considered a core element of the pluripotent Transcriptional network3,4,5,6,7. However, here we report that NANOG fluctuates in mouse embryonic stem cells. Transient downregulation of NANOG appears to predispose cells towards differentiation but does not mark commitment. By genetic deletion we show that, although they are prone to differentiate, embryonic stem cells can self-renew indefinitely in the permanent absence of NANOG. Expanded NANOG null cells colonize embryonic germ layers and exhibit multilineage differentiation both in fetal and adult chimaeras. Although they are also recruited to the germ line, primordial germ cells lacking NANOG fail to mature on reaching the genital ridge. This defect is rescued by repair of the mutant allele. Thus NANOG is dispensible for expression of somatic pluripotency but is specifically required for formation of germ cells. NANOG therefore acts primarily in construction of inner cell mass and germ cell states rather than in the housekeeping machinery of pluripotency. We surmise that NANOG stabilizes embryonic stem cells in culture by resisting or reversing alternative gene expression states.
Annie N.y. Cheung - One of the best experts on this subject based on the ideXlab platform.
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stem cell Transcription Factor NANOG in cancers is eternal youth a curse
Expert Opinion on Therapeutic Targets, 2016Co-Authors: Oscar G.w. Wong, Annie N.y. CheungAbstract:ABSTRACTIntroduction: Targeting cancer stem cells can be a more effective approach to treat cancer. NANOG is one of the key Factors for maintaining the self-renewal ability and pluripotency of stem cells, including cancer stem cells. Overexpression of NANOG has been observed in various human malignancies. Several reports have suggested that NANOG contributes to carcinogenesis by initiating and preserving cancer stem cells. It is obvious that NANOG is also involved in establishing other hallmarks of cancer such as uncontrolled cell growth, chemoresistance, metastasis, and immune evasion.Areas covered: This review will discuss the molecular properties and oncogenic roles of NANOG. The idea of using agents that inhibit the Transcription Factor to treat cancer is presented. Interfering with NANOG-mediated Transcriptions using small interfering RNA, Transcription Factor decoy, genome editing, and small-molecule inhibitors may provide novel strategies to target cancer stem cells.Expert opinion: As a pivotal con...
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Stem cell Transcription Factor NANOG in cancers – is eternal youth a curse?
Expert opinion on therapeutic targets, 2015Co-Authors: Oscar G.w. Wong, Annie N.y. CheungAbstract:ABSTRACTIntroduction: Targeting cancer stem cells can be a more effective approach to treat cancer. NANOG is one of the key Factors for maintaining the self-renewal ability and pluripotency of stem cells, including cancer stem cells. Overexpression of NANOG has been observed in various human malignancies. Several reports have suggested that NANOG contributes to carcinogenesis by initiating and preserving cancer stem cells. It is obvious that NANOG is also involved in establishing other hallmarks of cancer such as uncontrolled cell growth, chemoresistance, metastasis, and immune evasion.Areas covered: This review will discuss the molecular properties and oncogenic roles of NANOG. The idea of using agents that inhibit the Transcription Factor to treat cancer is presented. Interfering with NANOG-mediated Transcriptions using small interfering RNA, Transcription Factor decoy, genome editing, and small-molecule inhibitors may provide novel strategies to target cancer stem cells.Expert opinion: As a pivotal con...
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Abstract 4233: Dysregulated expression of stem cell Transcription Factor NANOG in development and progress of ovarian cancers
Tumor Biology, 2010Co-Authors: Michelle Ky Siu, Oscar G.w. Wong, Esther Sy Wong, Daniel Sh Kong, Kar Fai Tam, Hextan Y.s. Ngan, Annie N.y. CheungAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: Ovarian cancer is the most lethal of all gynecological malignacies due to its lack of symptoms at early stages. In addition, widespread intraperitoneal metastases and malignant ascites frequently develop. Therefore, it is very important to identify novel prognostic and therapeutic targets for this cancer. Many researchers believe that only a small subset of cancer cells are endowed with stem cell properties, which are responsible for tumor growth, metastatic progression and recurrence. NANOG is one of core Transcription Factors essential for the maintaining self-renewal and pluripotency in stem cells. This study investigated the clinical significance, functional roles and putative downstream targets of NANOG in ovarian cancer. Methods and Results: Differential protein expression profile of NANOG in clinical samples, including benign (n=6), borderline (n=7), carcinomas (n=97) and metastatic foci (n=24) were determined by immunohistochemistry. Differential mRNA expression pattern of NANOG in 3 normal ovarian epithelial cell lines, 16 ovarian cancer cell lines was assessed by quantitative real-time polymerase chain reaction. Subcellular localization of NANOG was performed by Western blotting. NANOG was found to be localized in the nucleus of ovarian cancers. High NANOG expression in ovarian cancers was significantly associated with high grade tumors, serous histological type and chemoresistance (p
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abstract 4233 dysregulated expression of stem cell Transcription Factor NANOG in development and progress of ovarian cancers
Cancer Research, 2010Co-Authors: Michelle Ky Siu, Oscar G.w. Wong, Esther Sy Wong, Daniel Sh Kong, Kar Fai Tam, Hextan Y.s. Ngan, Annie N.y. CheungAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: Ovarian cancer is the most lethal of all gynecological malignacies due to its lack of symptoms at early stages. In addition, widespread intraperitoneal metastases and malignant ascites frequently develop. Therefore, it is very important to identify novel prognostic and therapeutic targets for this cancer. Many researchers believe that only a small subset of cancer cells are endowed with stem cell properties, which are responsible for tumor growth, metastatic progression and recurrence. NANOG is one of core Transcription Factors essential for the maintaining self-renewal and pluripotency in stem cells. This study investigated the clinical significance, functional roles and putative downstream targets of NANOG in ovarian cancer. Methods and Results: Differential protein expression profile of NANOG in clinical samples, including benign (n=6), borderline (n=7), carcinomas (n=97) and metastatic foci (n=24) were determined by immunohistochemistry. Differential mRNA expression pattern of NANOG in 3 normal ovarian epithelial cell lines, 16 ovarian cancer cell lines was assessed by quantitative real-time polymerase chain reaction. Subcellular localization of NANOG was performed by Western blotting. NANOG was found to be localized in the nucleus of ovarian cancers. High NANOG expression in ovarian cancers was significantly associated with high grade tumors, serous histological type and chemoresistance (p<0.05). Importantly, NANOG was found to be highly expressed in ovarian cancer cell lines with metastasis-associated property and in clinical samples of metastatic foci. Elevated NANOG expression was associated with poor overall and disease-free survival in the univariate analysis. NANOG expression became one of the independent prognostic Factors in the multivariate analysis for overall but not disease-free survival. By Transwell migration and invasion assays, stable knockdown of NANOG in ovarian cancer cell line, OVCAR-3, impeded cell migration and invasion. Stable knockdown of NANOG also increased mRNA expression of E-cadherin (an essential epithelial mesenchymal transition marker, thus related to metastasis) and FOXO1A (an important gene related to chemoresistance). Conclusion: NANOG was associated with progression of ovarian tumors, patients’ overall survival and chemoresistance, suggesting that NANOG can be one of the potential prognostic markers and therapeutic molecular targets in ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4233.
Giovanna Roncador - One of the best experts on this subject based on the ideXlab platform.
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Lineage-restricted function of the pluripotency Factor NANOG in stratified epithelia
Nature communications, 2014Co-Authors: Daniela Piazzolla, Adelaida R. Palla, Cristina Pantoja, Marta Cañamero, Ignacio Pérez De Castro, Sagrario Ortega, Gonzalo Gómez-lópez, Orlando Domínguez, Diego Megías, Giovanna RoncadorAbstract:The Transcription Factor NANOG regulates self-renewal in pluripotent stem cells and cancer stem cells. Here the authors show that NANOG is expressed in mouse adult stratified epithelia, and its overexpression increases proliferation and aneuploidy and activates pathways associated to mitosis.
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Lineage-restricted function of the pluripotency Factor NANOG in stratified epithelia
Nature Communications, 2014Co-Authors: Daniela Piazzolla, Adelaida R. Palla, Cristina Pantoja, Marta Cañamero, Ignacio Pérez De Castro, Sagrario Ortega, Gonzalo Gómez-lópez, Orlando Domínguez, Diego Megías, Giovanna RoncadorAbstract:The Transcription Factor NANOG regulates self-renewal in pluripotent stem cells and cancer stem cells. Here the authors show that NANOG is expressed in mouse adult stratified epithelia, and its overexpression increases proliferation and aneuploidy and activates pathways associated to mitosis. NANOG is a pluripotency Transcription Factor in embryonic stem cells; however, its role in adult tissues remains largely unexplored. Here we show that mouse NANOG is selectively expressed in stratified epithelia, most notably in the oesophagus where the NANOG promoter is hypomethylated. Interestingly, inducible ubiquitous overexpression of NANOG in mice causes hyperplasia selectively in the oesophagus, in association with increased cell proliferation. NANOG Transcriptionally activates the mitotic programme, including Aurora A kinase ( Aurka ), in stratified epithelia, and endogenous NANOG directly binds to the Aurka promoter in primary keratinocytes. Interestingly, overexpression of NANOG or Aurka in mice increased proliferation and aneuploidy in the oesophageal basal epithelium. Finally, inactivation of NANOG in cell lines from oesophageal or head and neck squamous cell carcinomas (ESCCs or HNSCCs, respectively) results in lower levels of AURKA and decreased proliferation, and NANOG and AURKA expression are positively correlated in HNSCCs. Together, these results indicate that NANOG has a lineage-restricted mitogenic function in stratified epithelia.
Daniela Piazzolla - One of the best experts on this subject based on the ideXlab platform.
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Lineage-restricted function of the pluripotency Factor NANOG in stratified epithelia
Nature communications, 2014Co-Authors: Daniela Piazzolla, Adelaida R. Palla, Cristina Pantoja, Marta Cañamero, Ignacio Pérez De Castro, Sagrario Ortega, Gonzalo Gómez-lópez, Orlando Domínguez, Diego Megías, Giovanna RoncadorAbstract:The Transcription Factor NANOG regulates self-renewal in pluripotent stem cells and cancer stem cells. Here the authors show that NANOG is expressed in mouse adult stratified epithelia, and its overexpression increases proliferation and aneuploidy and activates pathways associated to mitosis.
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Lineage-restricted function of the pluripotency Factor NANOG in stratified epithelia
Nature Communications, 2014Co-Authors: Daniela Piazzolla, Adelaida R. Palla, Cristina Pantoja, Marta Cañamero, Ignacio Pérez De Castro, Sagrario Ortega, Gonzalo Gómez-lópez, Orlando Domínguez, Diego Megías, Giovanna RoncadorAbstract:The Transcription Factor NANOG regulates self-renewal in pluripotent stem cells and cancer stem cells. Here the authors show that NANOG is expressed in mouse adult stratified epithelia, and its overexpression increases proliferation and aneuploidy and activates pathways associated to mitosis. NANOG is a pluripotency Transcription Factor in embryonic stem cells; however, its role in adult tissues remains largely unexplored. Here we show that mouse NANOG is selectively expressed in stratified epithelia, most notably in the oesophagus where the NANOG promoter is hypomethylated. Interestingly, inducible ubiquitous overexpression of NANOG in mice causes hyperplasia selectively in the oesophagus, in association with increased cell proliferation. NANOG Transcriptionally activates the mitotic programme, including Aurora A kinase ( Aurka ), in stratified epithelia, and endogenous NANOG directly binds to the Aurka promoter in primary keratinocytes. Interestingly, overexpression of NANOG or Aurka in mice increased proliferation and aneuploidy in the oesophageal basal epithelium. Finally, inactivation of NANOG in cell lines from oesophageal or head and neck squamous cell carcinomas (ESCCs or HNSCCs, respectively) results in lower levels of AURKA and decreased proliferation, and NANOG and AURKA expression are positively correlated in HNSCCs. Together, these results indicate that NANOG has a lineage-restricted mitogenic function in stratified epithelia.
Oscar G.w. Wong - One of the best experts on this subject based on the ideXlab platform.
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stem cell Transcription Factor NANOG in cancers is eternal youth a curse
Expert Opinion on Therapeutic Targets, 2016Co-Authors: Oscar G.w. Wong, Annie N.y. CheungAbstract:ABSTRACTIntroduction: Targeting cancer stem cells can be a more effective approach to treat cancer. NANOG is one of the key Factors for maintaining the self-renewal ability and pluripotency of stem cells, including cancer stem cells. Overexpression of NANOG has been observed in various human malignancies. Several reports have suggested that NANOG contributes to carcinogenesis by initiating and preserving cancer stem cells. It is obvious that NANOG is also involved in establishing other hallmarks of cancer such as uncontrolled cell growth, chemoresistance, metastasis, and immune evasion.Areas covered: This review will discuss the molecular properties and oncogenic roles of NANOG. The idea of using agents that inhibit the Transcription Factor to treat cancer is presented. Interfering with NANOG-mediated Transcriptions using small interfering RNA, Transcription Factor decoy, genome editing, and small-molecule inhibitors may provide novel strategies to target cancer stem cells.Expert opinion: As a pivotal con...
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Stem cell Transcription Factor NANOG in cancers – is eternal youth a curse?
Expert opinion on therapeutic targets, 2015Co-Authors: Oscar G.w. Wong, Annie N.y. CheungAbstract:ABSTRACTIntroduction: Targeting cancer stem cells can be a more effective approach to treat cancer. NANOG is one of the key Factors for maintaining the self-renewal ability and pluripotency of stem cells, including cancer stem cells. Overexpression of NANOG has been observed in various human malignancies. Several reports have suggested that NANOG contributes to carcinogenesis by initiating and preserving cancer stem cells. It is obvious that NANOG is also involved in establishing other hallmarks of cancer such as uncontrolled cell growth, chemoresistance, metastasis, and immune evasion.Areas covered: This review will discuss the molecular properties and oncogenic roles of NANOG. The idea of using agents that inhibit the Transcription Factor to treat cancer is presented. Interfering with NANOG-mediated Transcriptions using small interfering RNA, Transcription Factor decoy, genome editing, and small-molecule inhibitors may provide novel strategies to target cancer stem cells.Expert opinion: As a pivotal con...
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Abstract 4233: Dysregulated expression of stem cell Transcription Factor NANOG in development and progress of ovarian cancers
Tumor Biology, 2010Co-Authors: Michelle Ky Siu, Oscar G.w. Wong, Esther Sy Wong, Daniel Sh Kong, Kar Fai Tam, Hextan Y.s. Ngan, Annie N.y. CheungAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: Ovarian cancer is the most lethal of all gynecological malignacies due to its lack of symptoms at early stages. In addition, widespread intraperitoneal metastases and malignant ascites frequently develop. Therefore, it is very important to identify novel prognostic and therapeutic targets for this cancer. Many researchers believe that only a small subset of cancer cells are endowed with stem cell properties, which are responsible for tumor growth, metastatic progression and recurrence. NANOG is one of core Transcription Factors essential for the maintaining self-renewal and pluripotency in stem cells. This study investigated the clinical significance, functional roles and putative downstream targets of NANOG in ovarian cancer. Methods and Results: Differential protein expression profile of NANOG in clinical samples, including benign (n=6), borderline (n=7), carcinomas (n=97) and metastatic foci (n=24) were determined by immunohistochemistry. Differential mRNA expression pattern of NANOG in 3 normal ovarian epithelial cell lines, 16 ovarian cancer cell lines was assessed by quantitative real-time polymerase chain reaction. Subcellular localization of NANOG was performed by Western blotting. NANOG was found to be localized in the nucleus of ovarian cancers. High NANOG expression in ovarian cancers was significantly associated with high grade tumors, serous histological type and chemoresistance (p
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abstract 4233 dysregulated expression of stem cell Transcription Factor NANOG in development and progress of ovarian cancers
Cancer Research, 2010Co-Authors: Michelle Ky Siu, Oscar G.w. Wong, Esther Sy Wong, Daniel Sh Kong, Kar Fai Tam, Hextan Y.s. Ngan, Annie N.y. CheungAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: Ovarian cancer is the most lethal of all gynecological malignacies due to its lack of symptoms at early stages. In addition, widespread intraperitoneal metastases and malignant ascites frequently develop. Therefore, it is very important to identify novel prognostic and therapeutic targets for this cancer. Many researchers believe that only a small subset of cancer cells are endowed with stem cell properties, which are responsible for tumor growth, metastatic progression and recurrence. NANOG is one of core Transcription Factors essential for the maintaining self-renewal and pluripotency in stem cells. This study investigated the clinical significance, functional roles and putative downstream targets of NANOG in ovarian cancer. Methods and Results: Differential protein expression profile of NANOG in clinical samples, including benign (n=6), borderline (n=7), carcinomas (n=97) and metastatic foci (n=24) were determined by immunohistochemistry. Differential mRNA expression pattern of NANOG in 3 normal ovarian epithelial cell lines, 16 ovarian cancer cell lines was assessed by quantitative real-time polymerase chain reaction. Subcellular localization of NANOG was performed by Western blotting. NANOG was found to be localized in the nucleus of ovarian cancers. High NANOG expression in ovarian cancers was significantly associated with high grade tumors, serous histological type and chemoresistance (p<0.05). Importantly, NANOG was found to be highly expressed in ovarian cancer cell lines with metastasis-associated property and in clinical samples of metastatic foci. Elevated NANOG expression was associated with poor overall and disease-free survival in the univariate analysis. NANOG expression became one of the independent prognostic Factors in the multivariate analysis for overall but not disease-free survival. By Transwell migration and invasion assays, stable knockdown of NANOG in ovarian cancer cell line, OVCAR-3, impeded cell migration and invasion. Stable knockdown of NANOG also increased mRNA expression of E-cadherin (an essential epithelial mesenchymal transition marker, thus related to metastasis) and FOXO1A (an important gene related to chemoresistance). Conclusion: NANOG was associated with progression of ovarian tumors, patients’ overall survival and chemoresistance, suggesting that NANOG can be one of the potential prognostic markers and therapeutic molecular targets in ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4233.