scholarly journals The Dynamic Changes of Transcription Factors During the Development Processes of Human Biparental and Uniparental Embryos

2021 ◽  
Vol 9 ◽  
Author(s):  
Chenxi Zhang ◽  
Conghui Li ◽  
Ling Yang ◽  
Lizhi Leng ◽  
Dragomirka Jovic ◽  
...  
Keyword(s):  
Stem Cell ◽  
Transcription Factors ◽  
Target Genes ◽  
Expression Profiles ◽  
Embryonic Stem ◽  
Dynamic Changes ◽  
Stem Cell Maintenance ◽  
Expression Model ◽  
Development Processes ◽  
High Degree

Previous studies have revealed that transcription factors (TFs) play important roles in biparental (BI) early human embryogenesis. However, the contribution of TFs during early uniparental embryo development is still largely unknown. Here we systematically studied the expression profiles of transcription factors in early embryonic development and revealed the dynamic changes of TFs in human biparental and uniparental embryogenesis by single-cell RNA sequencing (scRNA-seq). In general, the TF expression model of uniparental embryos showed a high degree of conformity with biparental embryos. The detailed network analysis of three different types of embryos identified that 10 out of 17 hub TFs were shared or specifically owned, such as ZNF480, ZNF581, PHB, and POU5F1, were four shared TFs, ZFN534, GTF3A, ZNF771, TEAD4, and LIN28A, were androgenic (AG) specific TFs, and ZFP42 was the only one parthenogenetic (PG) specific TF. All the four shared TFs were validated using human embryonic stem cell (hESC) differentiation experiments; most of their target genes are responsible for stem cell maintenance and differentiation. We also found that Zf-C2H2, HMG, and MYB were three dominant transcription factor families that appeared in early embryogenesis. Altogether, our work provides a comprehensive regulatory framework and better understanding of TF function in human biparental and uniparental embryogenesis.

scholarly journals Genes Involved in the Transcriptional Regulation of Pluripotency Are Expressed in Malignant Tumors of the Uterine Cervix and Can Induce Tumorigenic Capacity in a Nontumorigenic Cell Line

2019 ◽  
Vol 2019 ◽  
pp. 1-14
Author(s):  
Graciela Ruiz ◽  
Heriberto A. Valencia-González ◽  
Delia Pérez-Montiel ◽  
Felipe Muñoz ◽  
Rodolfo Ocadiz-Delgado ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cancer Stem Cell ◽  
Cell Line ◽  
Target Genes ◽  
Malignant Tumors ◽  
Expression Profiles ◽  
Ectopic Expression ◽  
Normal Tissues

Transcription factors OCT4, SOX2, KLF4, C-MYC, and NANOG (OSKM-N) regulate pluripotency and stemness, and their ectopic expression reprograms human and murine fibroblasts that constitute the key of regenerative medicine. To determine their contribution to cell transformation, we analyzed the gene expression profiles of these transcription factors in cervical cancer samples and found that they are preferentially expressed in the tumor component. Also, cancer stem cell-enriched cultures grown as sphere cultures showed overexpression of OSKM-N genes. Importantly, we observed that lentiviral-mediated transduction of these factors confers, to a nontumorigenic immortalized human cell line, properties of cancer stem cells as the ability to form tumors in a mouse model. When we performed a meta-analysis using microarray data from cervical cancer biopsies and normal tissues, we found that the expression of OSKM-N and some target genes allowed separating tumor and normal tissues between samples, which enhanced the importance of OSKM-N in the tumorigenesis. Finally, we analyzed and compared both transcript and protein expression profiles of these factors within a cohort of patients with cervical cancer. To our knowledge, this is the first time that the expression of OSKM-N is described to induce one of the main characteristics of the cancer stem cell, the tumorigenicity. And, more importantly, its exogenous expression in a nontumorigenic cell line is sufficient to induce a tumorigenic phenotype; furthermore, the differential expression of this transcription factor distinguishes tumor tissue and normal tissue in cervical samples.

scholarly journals The Importance of Ubiquitination and Deubiquitination in Cellular Reprogramming

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Bharathi Suresh ◽  
Junwon Lee ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna
Keyword(s):  
Stem Cell ◽  
Transcription Factors ◽  
Embryonic Stem ◽  
Cellular Reprogramming ◽  
Stem Cell Maintenance ◽  
Opposite Action ◽  
Induced Pluripotent ◽  
Related Proteins ◽  
Cell Maintenance

Ubiquitination of core stem cell transcription factors can directly affect stem cell maintenance and differentiation. Ubiquitination and deubiquitination must occur in a timely and well-coordinated manner to regulate the protein turnover of several stemness related proteins, resulting in optimal embryonic stem cell maintenance and differentiation. There are two switches: an E3 ubiquitin ligase enzyme that tags ubiquitin molecules to the target proteins for proteolysis and a second enzyme, the deubiquitinating enzyme (DUBs), that performs the opposite action, thereby preventing proteolysis. In order to maintain stemness and to allow for efficient differentiation, both ubiquitination and deubiquitination molecular switches must operate properly in a balanced manner. In this review, we have summarized the importance of the ubiquitination of core stem cell transcription factors, such as Oct3/4, c-Myc, Sox2, Klf4, Nanog, and LIN28, during cellular reprogramming. Furthermore, we emphasize the role of DUBs in regulating core stem cell transcriptional factors and their function in stem cell maintenance and differentiation. We also discuss the possibility of using DUBs, along with core transcription factors, to efficiently generate induced pluripotent stem cells. Our review provides a relatively new understanding regarding the importance of ubiquitination/deubiquitination of stem cell transcription factors for efficient cellular reprogramming.

scholarly journals The Role of Ubiquitination in Regulating Embryonic Stem Cell Maintenance and Cancer Development

2019 ◽  
Vol 20 (11) ◽  
pp. 2667 ◽  
Author(s):  
Dian Wang ◽  
Fan Bu ◽  
Weiwei Zhang
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Cancer Biology ◽  
Embryonic Stem ◽  
Developmental Defects ◽  
Stem Cell Maintenance ◽  
Substrate Protein ◽  
Cellular Events ◽  
Ubiquitin Conjugating Enzymes ◽  
Cell Maintenance

Ubiquitination regulates nearly every aspect of cellular events in eukaryotes. It modifies intracellular proteins with 76-amino acid polypeptide ubiquitin (Ub) and destines them for proteolysis or activity alteration. Ubiquitination is generally achieved by a tri-enzyme machinery involving ubiquitin activating enzymes (E1), ubiquitin conjugating enzymes (E2) and ubiquitin ligases (E3). E1 activates Ub and transfers it to the active cysteine site of E2 via a transesterification reaction. E3 coordinates with E2 to mediate isopeptide bond formation between Ub and substrate protein. The E1-E2-E3 cascade can create diverse types of Ub modifications, hence effecting distinct outcomes on the substrate proteins. Dysregulation of ubiquitination results in severe consequences and human diseases. There include cancers, developmental defects and immune disorders. In this review, we provide an overview of the ubiquitination machinery and discuss the recent progresses in the ubiquitination-mediated regulation of embryonic stem cell maintenance and cancer biology.

scholarly journals Screening Driving Transcription Factors in the Processing of Gastric Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Guangzhong Xu ◽  
Kai Li ◽  
Nengwei Zhang ◽  
Bin Zhu ◽  
Guosheng Feng
Keyword(s):  
Gastric Cancer ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Expression Profiles ◽  
Functional Enrichment ◽  
Regulatory Mechanisms ◽  
Integrated Analysis ◽  
Transcriptional Regulatory

Background. Construction of the transcriptional regulatory network can provide additional clues on the regulatory mechanisms and therapeutic applications in gastric cancer.Methods. Gene expression profiles of gastric cancer were downloaded from GEO database for integrated analysis. All of DEGs were analyzed by GO enrichment and KEGG pathway enrichment. Transcription factors were further identified and then a global transcriptional regulatory network was constructed.Results. By integrated analysis of the six eligible datasets (340 cases and 43 controls), a bunch of 2327 DEGs were identified, including 2100 upregulated and 227 downregulated DEGs. Functional enrichment analysis of DEGs showed that digestion was a significantly enriched GO term for biological process. Moreover, there were two important enriched KEGG pathways: cell cycle and homologous recombination. Furthermore, a total of 70 differentially expressed TFs were identified and the transcriptional regulatory network was constructed, which consisted of 566 TF-target interactions. The top ten TFs regulating most downstream target genes were BRCA1, ARID3A, EHF, SOX10, ZNF263, FOXL1, FEV, GATA3, FOXC1, and FOXD1. Most of them were involved in the carcinogenesis of gastric cancer.Conclusion. The transcriptional regulatory network can help researchers to further clarify the underlying regulatory mechanisms of gastric cancer tumorigenesis.

scholarly journals The Transcription Factor Zfp281 Controls Embryonic Stem Cell Pluripotency by Direct Activation and Repression of Target Genes

Stem Cells ◽  
2008 ◽  
Vol 26 (11) ◽  
pp. 2791-2799 ◽  
Author(s):  
Zheng-Xu Wang ◽  
Christina Hui-Leng Teh ◽  
Caroline Man-Yee Chan ◽  
Ci Chu ◽  
Michael Rossbach ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Target Genes ◽  
Embryonic Stem ◽  
Direct Activation ◽  
Stem Cell Pluripotency ◽  
Embryonic Stem Cell Pluripotency

Dynamic changes in energy metabolism upon embryonic stem cell differentiation support developmental toxicant identification

Toxicology ◽  
2014 ◽  
Vol 324 ◽  
pp. 76-87 ◽  
Author(s):  
Dorien A.M. van Dartel ◽  
Sjors H. Schulpen ◽  
Peter T. Theunissen ◽  
Annelies Bunschoten ◽  
Aldert H. Piersma ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Energy Metabolism ◽  
Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Dynamic Changes

194 EFFECT OF SMALL MOLECULE INHIBITORS ON Oct-4, Nanog, AND Sox-2 EXPRESSION IN BOVINE FETAL FIBROBLAST CELLS

2017 ◽  
Vol 29 (1) ◽  
pp. 206
Author(s):  
L. W. C. Gaspard ◽  
K. R. Bondioli
Keyword(s):  
Stem Cell ◽  
Small Molecules ◽  
Somatic Cell ◽  
Culture Medium ◽  
Target Genes ◽  
Embryonic Stem ◽  
Fibroblast Cells ◽  
Fetal Fibroblast ◽  
Transcript Levels ◽  
Cell Genome

Successful reprogramming of somatic cells towards pluripotency requires the epigenetic marks characteristic of the differentiated cell type first be erased in order to inactivate the somatic cell program and activate the embryonic program. However, the majority of cells that undergo reprogramming become trapped in a partially reprogrammed state that is characterised by the down-regulation of somatic cell marker genes, incomplete reactivation of pluripotency genes, maintenance of viral expression, and the inability to form chimeras. Several small molecules, which act on specific signaling pathways or chromatin modifications, have been shown to improve both the kinetics and efficiency of reprogramming. These chemical modifiers aid in overcoming the roadblocks encountered during the reprogramming process by inducing the necessary epigenetic modifications needed to silence the somatic cell genome and reactivate the embryonic stem cell genome. Chemical treatment of cells before reprogramming can remodel the epigenetic landscape to be more like that of embryonic stem cell by removing the repressive epigenetic marks and relaxing chromatin structure to allow the reprogramming factors easier access to target genes. In the present study, we assessed the effect of pretreatment with small molecules on the expression of Oct-4, Nanog, and Sox-2 in bovine fetal fibroblast cells. Chemical treatment consisted of 3 small molecules: PD0325901, a mitogen-activated protein kinase inhibitor; CHIR99021, a glycogen synthase kinase-3 inhibitor; and NuP0178 (NuPotential, Baton Rouge, LA, USA), a G9a histone methyltransferase inhibitor. Cells were seeded at a density of 0.7 × 106 and expanded before being divided evenly into 2 groups. Control cells were cultured in complete culture medium (DMEM with 10% fetal bovine serum), whereas treatment cells were cultured in complete culture medium containing 0.5 mM PD0325901, 3 mM CHIR99021, and 1.8 mM NuP0178. Messenger RNA was isolated from cell cultures using Dynabeads® mRNA DIRECT™ Kit (Dynal Inc., Lake Success, NY, USA) on Day 7 and 14, and the resulting RNA products were transcribed into cDNA using Bio-Rad iScript™ cDNA Synthesis Kit (Bio-Rad, Hercules, CA, USA). Quantitative RT–PCR was performed to measure transcript levels of Oct-4, Nanog, Sox-2, and poly adenylate polymerase in treated and untreated cells at Days 7 and 14. Transcript levels were quantified by relative quantification using the ΔΔCt method and expressed as ratios of target genes (Oct-4, Nanog, Sox-2) to the reference gene (PAP) and normalized against a calibrator consisting of untreated bovine fetal fibroblast cells. No difference in expression levels between untreated and treated cells was detected at either Day 7 or 14. Currently, we are utilising chromatin immunoprecipitation to examine chromatin and DNA methylation patterns around the promoters of Oct-4, Nanog, and Sox-2 to further elucidate the effects of treatment with this combination of small molecule inhibitors.

scholarly journals NANOG expression in human development and cancerogenesis

2020 ◽  
Vol 245 (5) ◽  
pp. 456-464 ◽  
Author(s):  
Gašper Grubelnik ◽  
Emanuela Boštjančič ◽  
Ana Pavlič ◽  
Marina Kos ◽  
Nina Zidar
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Human Development ◽  
Target Genes ◽  
Normal Development ◽  
Current Knowledge ◽  
Precancerous Lesions ◽  
Embryonic Stem ◽  
Predictive Marker ◽  
Nanog Expression

NANOG is an important stem cell transcription factor involved in human development and cancerogenesis. Its expression is complex and regulated on different levels. Moreover, NANOG protein might regulate hundreds of target genes at the same time. NANOG is crucial for preimplantation development phase and progressively decreases during embryonic stem cells differentiation, thus regulating embryonic and fetal development. Postnatally, NANOG is undetectable or expressed in very low amounts in the majority of human tissues. NANOG re-expression can be detected during cancerogenesis, already in precancerous lesions, with increasing levels of NANOG in high grade dysplasia. NANOG is believed to enable cancer cells to obtain stem-cell like properties, which are believed to be the source of expanding growth, tumor maintenance, metastasis formation, and tumor relapse. High NANOG expression in cancer is frequently associated with advanced stage, poor differentiation, worse overall survival, and resistance to treatment, and is therefore a promising prognostic and predictive marker. We summarize the current knowledge on the role of NANOG in cancerogenesis and development, including our own experience. We provide a critical overview of NANOG as a prognostic and diagnostic factor, including problems regarding its regulation and detection. Impact statement NANOG has emerged as a key stem cell transcription factor in normal development and cancerogenesis. It is generally regarded as a good prognostic and predictive factor in various human cancers. It is less known that it is expressed already at precancerous stages in various organs, suggesting that finally an ideal candidate diagnostic marker has been discovered, enabling to distinguish between true dysplasia and reactive atypia. NANOG regulation is complex, and new insights into our understanding of its regulation might provide important information for future development in a broad field of two entirely different processes, i.e. normal development and cancerogenesis, showing how a physiologic mechanism can be used and abused, transforming itself into a key mechanism of disease development and progression.

scholarly journals Loss of Mob1a/b impairs the differentiation of mouse embryonic stem cells into the three germ layer lineages

2019 ◽  
Vol 51 (11) ◽  
pp. 1-12 ◽  
Author(s):  
June Sung Bae ◽  
Sun Mi Kim ◽  
Yoon Jeon ◽  
Juyeon Sim ◽  
Ji Yun Jang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hippo Pathway ◽  
Critical Role ◽  
Embryonic Stem ◽  
Mouse Escs ◽  
Germ Layers ◽  
Stem Cell Maintenance ◽  
The Hippo Pathway ◽  
Cell Maintenance

AbstractThe Hippo pathway plays a crucial role in cell proliferation and apoptosis and can regulate stem cell maintenance and embryonic development. MOB kinase activators 1A and 1B (Mob1a/b) are key components of the Hippo pathway, whose homozygous deletion in mice causes early embryonic lethality at the preimplantation stage. To investigate the role of Mob1a/b in stem cell maintenance and differentiation, an embryonic stem cell (ESC) clone in which Mob1a/b could be conditionally depleted was generated and characterized. Although Mob1a/b depletion did not affect the stemness or proliferation of mouse ESCs, this depletion caused defects in differentiation into the three germ layers. Yap knockdown rescued the in vitro and in vivo defects in differentiation caused by Mob1a/b depletion, suggesting that differentiation defects caused by Mob1a/b depletion were Yap-dependent. In teratoma experiments, Yap knockdown in Mob1a/b-depleted ESCs partially restored defects in differentiation, indicating that hyperactivation of Taz, another effector of the Hippo pathway, inhibited differentiation into the three germ layers. Taken together, these results suggest that Mob1a/b or Hippo signaling plays a critical role in the differentiation of mouse ESCs into the three germ layers, which is dependent on Yap. These close relationship of the Hippo pathway with the differentiation of stem cells supports its potential as a therapeutic target in regenerative medicine.

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