The Experts below are selected from a list of 11499 Experts worldwide ranked by ideXlab platform
Humaira Gowher - One of the best experts on this subject based on the ideXlab platform.
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an epiGenetic switch regulates de novo dna methylation at a subset of Pluripotency Gene enhancers during embryonic stem cell differentiation
Nucleic Acids Research, 2016Co-Authors: Christopher J Petell, Lama Alabdi, San Miguel P, R Rose, Humaira GowherAbstract:Coordinated regulation of Gene expression that involves activation of lineage specific Genes and repression of Pluripotency Genes drives differentiation of embryonic stem cells (ESC). For complete repression of Pluripotency Genes during ESC differentiation, chromatin at their enhancers is silenced by the activity of the Lsd1-Mi2/NuRD complex. The mechanism/s that regulate DNA methylation at these enhancers are largely unknown. Here, we investigated the affect of the Lsd1-Mi2/NuRD complex on the dynamic regulatory switch that induces the local interaction of histone tails with the Dnmt3 ATRX-DNMT3-DNMT3L (ADD) domain, thus promoting DNA methylation at the enhancers of a subset of Pluripotency Genes. This is supported by previous structural studies showing a specific interaction between Dnmt3-ADD domain with H3K4 unmethylated histone tails that is disrupted by histone H3K4 methylation and histone acetylation. Our data suggest that Dnmt3a activity is triggered by Lsd1-Mi2/NuRD-mediated histone deacetylation and demethylation at these Pluripotency Gene enhancers when they are inactivated during mouse ESC differentiation. Using Dnmt3 knockout ESCs and the inhibitors of Lsd1 and p300 histone modifying enzymes during differentiation of E14Tg2A and ZHBTc4 ESCs, our study systematically reveals this mechanism and establishes that Dnmt3a is both reader and effector of the epiGenetic state at these target sites.
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an epiGenetic switch regulates de novo dna methylation at Pluripotency Gene enhancers
The FASEB Journal, 2016Co-Authors: Christopher J Petell, Lama Alabdi, R Rose, Phillip San Miguel, Humaira GowherAbstract:Coordinated regulation of Gene expression which involves activation of lineage specific Genes and repression of Pluripotency Genes drives differentiation of embryonic stem cells. For the complete r...
Adrian Kee Keong Teo - One of the best experts on this subject based on the ideXlab platform.
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defective insulin receptor signaling in hpscs skews Pluripotency and negatively perturbs neural differentiation
Journal of Biological Chemistry, 2021Co-Authors: Adrian Kee Keong Teo, Linh Nguyen, Manoj K Gupta, Hwee Hui Lau, Larry Sai Weng Loo, Nicholas Jackson, Chang Siang Lim, William Mallard, Marina A GritsenkoAbstract:Human embryonic stem cells are a type of pluripotent stem cells (hPSCs) that are used to investigate their differentiation into diverse mature cell types for molecular studies. The mechanisms underlying insulin receptor (IR)-mediated signaling in the maintenance of human pluripotent stem cell (hPSC) identity and cell fate specification are not fully understood. Here, we used two independent shRNAs to stably knock down IRs in two hPSC lines that represent pluripotent stem cells (hPSCs) and explored the consequences on expression of key proteins in pathways linked to proliferation and differentiation. We consistently observed lowered pAKT in contrast to increased pERK1/2 and a concordant elevation in Pluripotency Gene expression. ERK2 chromatin immunoprecipitation, luciferase assays and ERK1/2 inhibitors established direct causality between ERK1/2 and OCT4 expression. Importantly, RNA-sequencing analyses indicated a dysregulation of Genes involved in cell differentiation and organismal development. Mass spectrometry-based proteomic analyses further confirmed a global down-regulation of extracellular matrix (ECM) proteins. Subsequent differentiation towards the neural lineage reflected alterations in SOX1+PAX6+ neuroectoderm and FOXG1+ cortical neuron marker expression, and protein localization. Collectively, our data underscore the role of IR-mediated signaling in maintaining Pluripotency, the ECM necessary for the stem cell niche and regulating cell fate specification including the neural lineage.
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defective insulin receptor signaling in hpscs skews Pluripotency and negatively perturbs neural differentiation
Journal of Biological Chemistry, 2021Co-Authors: Adrian Kee Keong Teo, Linh Nguyen, Manoj K Gupta, Hwee Hui Lau, Larry Sai Weng LooAbstract:Human embryonic stem cells are a type of pluripotent stem cells (hPSCs) that are used to investigate their differentiation into diverse mature cell types for molecular studies. The mechanisms underlying insulin receptor (IR)-mediated signaling in the maintenance of human pluripotent stem cell (hPSC) identity and cell fate specification are not fully understood. Here, we used two independent shRNAs to stably knock down IRs in two hPSC lines that represent pluripotent stem cells and explored the consequences on expression of key proteins in pathways linked to proliferation and differentiation. We consistently observed lowered pAKT in contrast to increased pERK1/2 and a concordant elevation in Pluripotency Gene expression. ERK2 chromatin immunoprecipitation, luciferase assays, and ERK1/2 inhibitors established direct causality between ERK1/2 and OCT4 expression. Of importance, RNA sequencing analyses indicated a dysregulation of Genes involved in cell differentiation and organismal development. Mass spectrometry–based proteomic analyses further confirmed a global downregulation of extracellular matrix proteins. Subsequent differentiation toward the neural lineage reflected alterations in SOX1+PAX6+ neuroectoderm and FOXG1+ cortical neuron marker expression and protein localization. Collectively, our data underscore the role of IR-mediated signaling in maintaining Pluripotency, the extracellular matrix necessary for the stem cell niche, and regulating cell fate specification including the neural lineage.
Jyuan Wei Hsu - One of the best experts on this subject based on the ideXlab platform.
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involvement of collagen xvii in Pluripotency Gene expression and metabolic reprogramming of lung cancer stem cells
Journal of Biomedical Science, 2020Co-Authors: Han Shui Hsu, Chen Chi Liu, Jiun Han Lin, Tien Wei Hsu, Jyuan Wei HsuAbstract:Recent advancements in cancer biology field suggest that glucose metabolism is a potential target for cancer treatment. However, little if anything is known about the metabolic profile of cancer stem cells (CSCs) and the related underlying mechanisms. The metabolic phenotype in lung CSC was first investigated. The role of collagen XVII, a putative stem cell or CSC candidate marker, in regulating metabolic reprogramming in lung CSC was subsequently studied. Through screening the Genes involved in glycolysis, we identified the downstream targets of collagen XVII that were involved in metabolic reprogramming of lung CSCs. Collagen XVII and its downstream targets were then used to predict the prognosis of lung cancer patients. We showed that an aberrant upregulation of glycolysis and oxidative phosphorylation in lung CSCs is associated with the maintenance of CSC-like features, since blocking glycolysis and oxidative phosphorylation reduces sphere formation, chemoresistance, and tumorigenicity. We also showed that the Oct4-hexokinase 2 (HK2) pathway activated by collagen XVII-laminin-332 through FAK-PI3K/AKT-GSB3β/β-catenin activation induced the upregulation of glycolysis and maintenance of CSC-like features. Finally, we showed that collagen XVII, Oct4, and HK2 could be valuable markers to predict the prognosis of lung cancer patients. These data suggest the Oct4-HK2 pathway regulated by collagen XVII plays an important role in metabolic reprogramming and maintenance of CSC-like features in lung CSCs, which may aid in the development of new strategies in cancer treatment.
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involvement of collagen xvii in Pluripotency Gene expression and metabolic reprogramming of lung cancer stem cells
Social Science Research Network, 2019Co-Authors: Han Shui Hsu, Chen Chi Liu, Jiun Han Lin, Tien Wei Hsu, Jyuan Wei Hsu, Shihchieh HungAbstract:Background: Recent advancements in cancer biology field suggest that glucose metabolism is a potential target for cancer treatment. However, little if anything is known about the metabolic profile of cancer stem cells (CSCs) and the related underlying mechanisms. Methods: The metabolic phenotype in lung CSC was first investigated. The role of collagen XVII, a putative stem cell or CSC candidate marker, in regulating metabolic reprogramming in lung CSC was subsequently studied. Through screening the Genes involved in glycolysis, we identified the downstream targets of collagen XVII that were involved in metabolic reprogramming of lung CSCs. Collagen XVII and its downstream targets were then used to predict the prognosis of lung cancer patients. Findings: We showed that an aberrant upregulation of glycolysis and oxidative phosphorylation in lung CSCs is associated with the maintenance of CSC-like features, since blocking glycolysis and oxidative phosphorylation reduces sphere formation, chemoresistance, and tumorigenicity. We also showed that the Oct4-hexokinase 2 (HK2) pathway activated by collagen XVII-laminin 5 through FAK-PI3K/AKT-GSB3β/β-catenin activation induced the upregulation of glycolysis and maintenance of CSC-like features. Finally, we showed that collagen XVII, Oct4, and HK2 could be valuable markers to predict the prognosis of lung cancer patients. Interpretation: These data suggest the Oct4-HK2 pathway regulated by collagen XVII plays an important role in metabolic reprogramming and maintenance of CSC-like features in lung CSCs, which may aid in the development of new strategies in cancer treatment. Funding Statement: This work was supported by the Ministry of Science and Technology (MOST 106-2314-B-010-028-MY3, MOST 106-2314-B-075-030-MY3, MOST 106-2321-B-039-003) and Taipei Veteran General Hospital (V107C-182, V106C-060, V106C-174). This work was also financially supported by the “Drug Development Center, China Medical University" from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: Protocols involving mice were approved by the Institutional Animal Committee of Taipei Veterans General Hospital.
Christopher J Petell - One of the best experts on this subject based on the ideXlab platform.
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an epiGenetic switch regulates de novo dna methylation at a subset of Pluripotency Gene enhancers during embryonic stem cell differentiation
Nucleic Acids Research, 2016Co-Authors: Christopher J Petell, Lama Alabdi, San Miguel P, R Rose, Humaira GowherAbstract:Coordinated regulation of Gene expression that involves activation of lineage specific Genes and repression of Pluripotency Genes drives differentiation of embryonic stem cells (ESC). For complete repression of Pluripotency Genes during ESC differentiation, chromatin at their enhancers is silenced by the activity of the Lsd1-Mi2/NuRD complex. The mechanism/s that regulate DNA methylation at these enhancers are largely unknown. Here, we investigated the affect of the Lsd1-Mi2/NuRD complex on the dynamic regulatory switch that induces the local interaction of histone tails with the Dnmt3 ATRX-DNMT3-DNMT3L (ADD) domain, thus promoting DNA methylation at the enhancers of a subset of Pluripotency Genes. This is supported by previous structural studies showing a specific interaction between Dnmt3-ADD domain with H3K4 unmethylated histone tails that is disrupted by histone H3K4 methylation and histone acetylation. Our data suggest that Dnmt3a activity is triggered by Lsd1-Mi2/NuRD-mediated histone deacetylation and demethylation at these Pluripotency Gene enhancers when they are inactivated during mouse ESC differentiation. Using Dnmt3 knockout ESCs and the inhibitors of Lsd1 and p300 histone modifying enzymes during differentiation of E14Tg2A and ZHBTc4 ESCs, our study systematically reveals this mechanism and establishes that Dnmt3a is both reader and effector of the epiGenetic state at these target sites.
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an epiGenetic switch regulates de novo dna methylation at Pluripotency Gene enhancers
The FASEB Journal, 2016Co-Authors: Christopher J Petell, Lama Alabdi, R Rose, Phillip San Miguel, Humaira GowherAbstract:Coordinated regulation of Gene expression which involves activation of lineage specific Genes and repression of Pluripotency Genes drives differentiation of embryonic stem cells. For the complete r...
Maria Paula Faillace - One of the best experts on this subject based on the ideXlab platform.
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Injury-induced purinergic signalling molecules upregulate Pluripotency Gene expression and mitotic activity of progenitor cells in the zebrafish retina
Purinergic Signalling, 2017Co-Authors: Matías P. Medrano, Claudio A. Bejarano, Ariadna G. Battista, Graciela D. Venera, Ramón O. Bernabeu, Maria Paula FaillaceAbstract:Damage in fish activates retina repair that restores sight. The purinergic signalling system serves multiple homeostatic functions and has been implicated in cell cycle control of progenitor cells in the developing retina. We examined whether changes in the expression of purinergic molecules were instrumental in the proliferative phase after injury of adult zebrafish retinas with ouabain. P2RY_1 messenger RNA (mRNA) increased early after injury and showed maximal levels at the time of peak progenitor cell proliferation. Extracellular nucleotides, mainly ADP, regulate P2RY_1 transcriptional and protein expression. The injury-induced upregulation of P2RY_1 is mediated by an autoregulated mechanism. After injury, the transcriptional expression of ecto-nucleotidases and ecto-ATPases also increased and ecto-ATPase activity inhibitors decreased Müller glia-derived progenitor cell amplification. Inhibition of P2RY_1 endogenous activation prevented progenitor cell proliferation at two intervals after injury: one in which progenitor Müller glia mitotically activates and the second one in which Müller glia-derived progenitor cells amplify. ADPβS induced the expression of lin28a and ascl1a Genes in mature regions of uninjured retinas. The expression of these Genes, which regulate multipotent Müller glia reprogramming, was significantly inhibited by blocking the endogenous activation of P2RY_1 early after injury. We consistently observed that the number of glial fibrillary acidic protein-BrdU-positive Müller cells after injury was larger in the absence than in the presence of the P2RY_1 antagonist. Ecto-ATPase activity inhibitors or P2RY_1-specific antagonists did not modify apoptotic cell death at the time of peak progenitor cell proliferation. The results suggested that ouabain injury upregulates specific purinergic signals which stimulates multipotent progenitor cell response.