scholarly journals Integration of Signaling Pathways with the Epigenetic Machinery in the Maintenance of Stem Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Luca Fagnocchi ◽  
Stefania Mazzoleni ◽  
Alessio Zippo
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Signaling Pathways ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Transcriptional Regulatory Network ◽  
Specific Gene ◽  
Differentiation Potential ◽  
Cell Identity ◽  
Epigenetic Machinery

Stem cells balance their self-renewal and differentiation potential by integrating environmental signals with the transcriptional regulatory network. The maintenance of cell identity and/or cell lineage commitment relies on the interplay of multiple factors including signaling pathways, transcription factors, and the epigenetic machinery. These regulatory modules are strongly interconnected and they influence the pattern of gene expression of stem cells, thus guiding their cellular fate. Embryonic stem cells (ESCs) represent an invaluable tool to study this interplay, being able to indefinitely self-renew and to differentiate towards all three embryonic germ layers in response to developmental cues. In this review, we highlight those mechanisms of signaling to chromatin, which regulate chromatin modifying enzymes, histone modifications, and nucleosome occupancy. In addition, we report the molecular mechanisms through which signaling pathways affect both the epigenetic and the transcriptional state of ESCs, thereby influencing their cell identity. We propose that the dynamic nature of oscillating signaling and the different regulatory network topologies through which those signals are encoded determine specific gene expression programs, leading to the fluctuation of ESCs among multiple pluripotent states or to the establishment of the necessary conditions to exit pluripotency.

scholarly journals Perivascular-Derived Mesenchymal Stem Cells

2019 ◽  
Vol 98 (10) ◽  
pp. 1066-1072 ◽  
Author(s):  
V. Yianni ◽  
P.T. Sharpe
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Dental Pulp ◽  
Molecular Mechanisms ◽  
Lineage Tracing ◽  
Specific Gene ◽  
Genetic Lineage ◽  
Differentiation Potential

Cells have been identified in postnatal tissues that, when isolated from multiple mesenchymal compartments, can be stimulated in vitro to give rise to cells that resemble mature mesenchymal phenotypes, such as odontoblasts, osteoblasts, adipocytes, and myoblasts. This has made these adult cells, collectively called mesenchymal stem cells (MSCs), strong candidates for fields such as tissue engineering and regenerative medicine. Based on evidence from in vivo genetic lineage–tracing studies, pericytes have been identified as a source of MSC precursors in vivo in multiple organs, in response to injury or during homeostasis. Questions of intense debate and interest in the field of tissue engineering and regenerative studies include the following: 1) Are all pericytes, irrespective of tissue of isolation, equal in their differentiation potential? 2) What are the mechanisms that regulate the differentiation of MSCs? To gain a better understanding of the latter, recent work has utilized ChIP-seq (chromatin immunoprecipitation followed by sequencing) to reconstruct histone landscapes. This indicated that for dental pulp pericytes, the odontoblast-specific gene Dspp was found in a transcriptionally permissive state, while in bone marrow pericytes, the osteoblast-specific gene Runx2 was primed for expression. RNA sequencing has also been utilized to further characterize the 2 pericyte populations, and results highlighted that dental pulp pericytes are already precommitted to an odontoblast fate based on enrichment analysis indicating overrepresentation of key odontogenic genes. Furthermore, ChIP-seq analysis of the polycomb repressive complex 1 component RING1B indicated that this complex is likely to be involved in inhibiting inappropriate differentiation, as it localized to a number of loci of key transcription factors that are needed for the induction of adipogenesis, chondrogenesis, or myogenesis. In this review, we highlight recent data elucidating molecular mechanisms that indicate that pericytes can be tissue-specific precommitted MSC precursors in vivo and that this precommitment is a major driving force behind MSC differentiation.

scholarly journals Functional Modules Analysis and Hub Gene Prognostic Values Evaluation Based on Co-Expression Network in Gastric Cancer

2021 ◽  
Author(s):  
Yujia Liu ◽  
Xiaoping Hu ◽  
Zongfu Pan ◽  
Yuchen Jiang ◽  
Dandan Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Transcriptional Regulatory Network ◽  
Receptor Interaction ◽  
Ppi Network ◽  
Hub Gene ◽  
Transcriptional Regulatory ◽  
Key Nodes

Abstract Background: Gastric cancer is one of the most common fatal disease worldwide, but its mechanism and therapeutic targets are still unclear. In this study, we have analyzed the differences in gene modules and key pathways in gastric cancer patients, then elaborated the mechanism and effective treatment of gastric cancer with microarray data from the gene expression omnibus(GEO) database. Methods: GEO2R tools were used to identify differential expression genes (DEGs), String database was employed to construct a protein-protein interaction (PPI) network. We imported the PPI network into the Cytoscape software to find key nodes, and employed statistical approach of MCODE to cluster genes. After that the ClueGO was used to enrich and annotate the pathways of key modules. To investigate the relationship between the upstream regulator and hub genes, the transcriptional regulatory network was built based on TFCAT database. Results: 63 characteristic genes of gastric cancer are involved in regulation of ECM-receptor interaction, focal adhesion and protein digestion and absorption. SPARC, FN1, BGN and COL1A2 are four key nodes relating to tumor proliferation and metastasis, and their expression were strongly associated with poor survival (p<0.05). 13 transcription factors including PRRX1 have remarkable changes in gastric cancer, which may play a key role in hub gene regulation. Conclusions: The present study defined the gene expression characteristics and transcriptional regulatory network that promote our understanding of the molecular mechanisms underlying the development of gastric cancer, and might provide new insights into targeted therapy and prognostic markers for the personalized treatment of gastric cancer.

scholarly journals Genetic and pharmacological inactivation of adenosine A2A receptor reveals an Egr-2-mediated transcriptional regulatory network in the mouse striatum

2005 ◽  
Vol 23 (1) ◽  
pp. 89-102 ◽  
Author(s):  
Liqun Yu ◽  
Peter M. Haverty ◽  
Juliana Mariani ◽  
Yumei Wang ◽  
Hai-Ying Shen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Transcriptional Regulatory Network ◽  
Expression Profiles ◽  
Mrna Level ◽  
Gene Expression Profiles ◽  
Bioinformatics Analyses ◽  
Mouse Striatum ◽  
Transcriptional Regulatory

The adenosine A2A receptor (A2AR) is highly expressed in the striatum, where it modulates motor and emotional behaviors. We used both microarray and bioinformatics analyses to compare gene expression profiles by genetic and pharmacological inactivation of A2AR and inferred an A2AR-controlled transcription network in the mouse striatum. A comparison between vehicle (VEH)-treated A2AR knockout (KO) mice (A2AR KO-VEH) and wild-type (WT) mice (WT-VEH) revealed 36 upregulated genes that were partially mimicked by treatment with SCH-58261 (SCH; an A2AR antagonist) and 54 downregulated genes that were not mimicked by SCH treatment. We validated the A2AR as a specific drug target for SCH by comparing A2AR KO-SCH and A2AR KO-VEH groups. The unique downregulation effect of A2AR KO was confirmed by comparing A2AR KO-SCH with WT-SCH gene groups. The distinct striatal gene expression profiles induced by A2AR KO and SCH should provide clues to the molecular mechanisms underlying the different phenotypes observed after genetic and pharmacological inactivation of A2AR. Furthermore, bioinformatics analysis discovered that Egr-2 binding sites were statistically overrepresented in the proximal promoters of A2AR KO-affected genes relative to the unaffected genes. This finding was further substantiated by the demonstration that the Egr-2 mRNA level increased in the striatum of both A2AR KO and SCH-treated mice and that striatal Egr-2 binding activity in the promoters of two A2AR KO-affected genes was enhanced in A2AR KO mice as assayed by chromatin immunoprecipitation. Taken together, these results strongly support the existence of an Egr-2-directed transcriptional regulatory network controlled by striatal A2ARs.

scholarly journals Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

2016 ◽  
Vol 113 (42) ◽  
pp. 11871-11876 ◽  
Author(s):  
Chaochen Wang ◽  
Ji-Eun Lee ◽  
Binbin Lai ◽  
Todd S. Macfarlan ◽  
Shiliyang Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Cell Fate ◽  
Control Cell ◽  
Embryonic Stem ◽  
Specific Gene ◽  
Cell Identity ◽  
Identity Maintenance ◽  
Cell Type Specific ◽  
Induced Pluripotent

Transcriptional enhancers control cell-type–specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes. As a result, MLL4 is dispensable for cell-identity gene expression and self-renewal in ESCs. In contrast, MLL4 is required for enhancer-binding of H3K27 acetyltransferase p300, enhancer activation, and induction of cell-identity genes during ESC differentiation. MLL4 protein, rather than MLL4-mediated H3K4 methylation, controls p300 recruitment to enhancers. We also show that, in somatic cells, MLL4 is dispensable for maintaining cell identity but essential for reprogramming into induced pluripotent stem cells. These results indicate that, although enhancer priming by MLL4 is dispensable for cell-identity maintenance, it controls cell fate transition by orchestrating p300-mediated enhancer activation.

scholarly journals Functional Modules Analysis and Hub Gene Prognostic Values Evaluation Based on Co-Expression Network in Gastric Cancer

2021 ◽  
Author(s):  
Yujia Liu ◽  
Xiaoping Hu ◽  
Zongfu Pan ◽  
Yuchen Jiang ◽  
Dandan Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Transcriptional Regulatory Network ◽  
Receptor Interaction ◽  
Ppi Network ◽  
Hub Gene ◽  
Transcriptional Regulatory ◽  
Key Nodes

Abstract Background: Gastric cancer is one of the most common fatal disease worldwide, but its mechanism and therapeutic targets are still unclear. In this study, we have analyzed the differences in gene modules and key pathways in gastric cancer patients, then elaborated the mechanism and effective treatment of gastric cancer with microarray data from the gene expression omnibus(GEO) database.Methods: GEO2R tools were used to identify differential expression genes (DEGs), String database was employed to construct a protein-protein interaction (PPI) network. We imported the PPI network into the Cytoscape software to find key nodes, and employed statistical approach of MCODE to cluster genes. After that the ClueGO was used to enrich and annotate the pathways of key modules. To investigate the relationship between the upstream regulator and hub genes, the transcriptional regulatory network was built based on TFCAT database.Results: 63 characteristic genes of gastric cancer are involved in regulation of ECM-receptor interaction, focal adhesion and protein digestion and absorption. SPARC, FN1, BGN and COL1A2 are four key nodes relating to tumor proliferation and metastasis, and their expression were strongly associated with poor survival (p<0.05). 13 transcription factors including PRRX1 have remarkable changes in gastric cancer, which may play a key role in hub gene regulation.Conclusions: The present study defined the gene expression characteristics and transcriptional regulatory network that promote our understanding of the molecular mechanisms underlying the development of gastric cancer, and might provide new insights into targeted therapy and prognostic markers for the personalized treatment of gastric cancer.

Recent approaches for isolating and culturing mouse bone marrow-derived mesenchymal stromal stem cells

2020 ◽  
Vol 15 ◽  
Author(s):  
Basem M. Abdallah ◽  
Hany M. Khattab
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Molecular Mechanisms ◽  
Replicative Senescence ◽  
Cellular Heterogeneity ◽  
High Yield ◽  
Mouse Strains ◽  
Mouse Bone Marrow ◽  
Differentiation Potential ◽  
Stromal Stem Cells

: The isolation and culture of murine bone marrow-derived mesenchymal stromal stem cells (mBMSCs) have attracted great interest in terms of the pre-clinical applications of stem cells in tissue engineering and regenerative medicine. In addition, culturing mBMSCs is important for studying the molecular mechanisms of bone remodelling using relevant transgenic mice. Several factors have created challenges in the isolation and high-yield expansion of homogenous mBMSCs; these factors include low frequencies of bone marrow-derived mesenchymal stromal stem cells (BMSCs) in bone marrow, variation among inbred mouse strains, contamination with haematopoietic progenitor cells (HPCs), the replicative senescence phenotype and cellular heterogeneity. In this review, we provide an overview of nearly all protocols used for isolating and culturing mBMSCs with the aim of clarifying the most important guidelines for culturing highly purified mBMSC populations retaining in vitro and in vivo differentiation potential.

scholarly journals Modulation of Human Mesenchymal Stem Cells by Electrical Stimulation Using an Enzymatic Biofuel Cell

Catalysts ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 62
Author(s):  
Won-Yong Jeon ◽  
Seyoung Mun ◽  
Wei Beng Ng ◽  
Keunsoo Kang ◽  
Kyudong Han ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Electrical Stimulation ◽  
Regenerative Medicine ◽  
Cell Morphology ◽  
Electrical Current ◽  
Specific Gene ◽  
Next Generation ◽  
The Impact

Enzymatic biofuel cells (EBFCs) have excellent potential as components in bioelectronic devices, especially as active biointerfaces to regulate stem cell behavior for regenerative medicine applications. However, it remains unclear to what extent EBFC-generated electrical stimulation can regulate the functional behavior of human adipose-derived mesenchymal stem cells (hAD-MSCs) at the morphological and gene expression levels. Herein, we investigated the effect of EBFC-generated electrical stimulation on hAD-MSC cell morphology and gene expression using next-generation RNA sequencing. We tested three different electrical currents, 127 ± 9, 248 ± 15, and 598 ± 75 nA/cm2, in mesenchymal stem cells. We performed transcriptome profiling to analyze the impact of EBFC-derived electrical current on gene expression using next generation sequencing (NGS). We also observed changes in cytoskeleton arrangement and analyzed gene expression that depends on the electrical stimulation. The electrical stimulation of EBFC changes cell morphology through cytoskeleton re-arrangement. In particular, the results of whole transcriptome NGS showed that specific gene clusters were up- or down-regulated depending on the magnitude of applied electrical current of EBFC. In conclusion, this study demonstrates that EBFC-generated electrical stimulation can influence the morphological and gene expression properties of stem cells; such capabilities can be useful for regenerative medicine applications such as bioelectronic devices.

scholarly journals MicroRNA treatment modulates osteogenic differentiation potential of mesenchymal stem cells derived from human chorion and placenta

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kulisara Marupanthorn ◽  
Chairat Tantrawatpan ◽  
Pakpoom Kheolamai ◽  
Duangrat Tantikanlayaporn ◽  
Sirikul Manochantr
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Transcription Factor ◽  
Osteogenic Differentiation ◽  
Differentiation Potential ◽  
Osteogenic Gene Expression ◽  
Osteogenic Gene

AbstractMesenchymal stem cells (MSCs) are important in regenerative medicine because of their potential for multi-differentiation. Bone marrow, chorion and placenta have all been suggested as potential sources for clinical application. However, the osteogenic differentiation potential of MSCs derived from chorion or placenta is not very efficient. Bone morphogenetic protein-2 (BMP-2) plays an important role in bone development. Its effect on osteogenic augmentation has been addressed in several studies. Recent studies have also shown a relationship between miRNAs and osteogenesis. We hypothesized that miRNAs targeted to Runt-related transcription factor 2 (Runx-2), a major transcription factor of osteogenesis, are responsible for regulating the differentiation of MSCs into osteoblasts. This study examines the effect of BMP-2 on the osteogenic differentiation of MSCs isolated from chorion and placenta in comparison to bone marrow-derived MSCs and investigates the role of miRNAs in the osteogenic differentiation of MSCs from these sources. MSCs were isolated from human bone marrow, chorion and placenta. The osteogenic differentiation potential after BMP-2 treatment was examined using ALP staining, ALP activity assay, and osteogenic gene expression. Candidate miRNAs were selected and their expression levels during osteoblastic differentiation were examined using real-time RT-PCR. The role of these miRNAs in osteogenesis was investigated by transfection with specific miRNA inhibitors. The level of osteogenic differentiation was monitored after anti-miRNA treatment. MSCs isolated from chorion and placenta exhibited self-renewal capacity and multi-lineage differentiation potential similar to MSCs isolated from bone marrow. BMP-2 treated MSCs showed higher ALP levels and osteogenic gene expression compared to untreated MSCs. All investigated miRNAs (miR-31, miR-106a and miR148) were consistently downregulated during the process of osteogenic differentiation. After treatment with miRNA inhibitors, ALP activity and osteogenic gene expression increased over the time of osteogenic differentiation. BMP-2 has a positive effect on osteogenic differentiation of chorion- and placenta-derived MSCs. The inhibition of specific miRNAs enhanced the osteogenic differentiation capacity of various MSCs in culture and this strategy might be used to promote bone regeneration. However, further in vivo experiments are required to assess the validity of this approach.

scholarly journals Set1 Targets Genes with Essential Identity and Tumor-Suppressing Functions in Planarian Stem Cells

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1182
Author(s):  
Prince Verma ◽  
Court K. M. Waterbury ◽  
Elizabeth M. Duncan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mammalian Cells ◽  
Cell Function ◽  
Genotoxic Stress ◽  
Specific Gene ◽  
Cell Identity ◽  
Chromatin Signature ◽  
Lysine Methyltransferase

Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine 4 trimethylation (H3K4me3) signal across the planarian genome to determine if the broad H3K4me3 chromatin signature that marks essential cell identity genes and TSGs in mammalian cells is conserved in this valuable model of in vivo stem cell function. We find that this signature is indeed conserved on the planarian genome and that the lysine methyltransferase Set1 is largely responsible for creating it at both cell identity and putative TSG loci. In addition, we show that depletion of set1 in planarians induces stem cell phenotypes that suggest loss of TSG function, including hyperproliferation and an abnormal DNA damage response (DDR). Importantly, this work establishes that Set1 targets specific gene loci in planarian stem cells and marks them with a conserved chromatin signature. Moreover, our data strongly suggest that Set1 activity at these genes has important functional consequences both during normal homeostasis and in response to genotoxic stress.

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