scholarly journals Platr4 is an ESC-specific lncRNA that exhibits its function downstream on meso/endoderm lineage commitment

2021 ◽  
Author(s):  
Rasmani Hazra ◽  
Lily Brine ◽  
Libia Garcia ◽  
Brian Benz ◽  
Napon Chirathivat ◽  
...  
Keyword(s):  
Disease Modeling ◽  
Embryonic Stem ◽  
Tissue Growth ◽  
Lineage Commitment ◽  
Developmentally Regulated ◽  
Downstream Target ◽  
Lineage Differentiation ◽  
Downstream Target Gene ◽  
Undifferentiated Escs ◽  
Transcription Factor 4

The mammalian genome encodes thousands of long non-coding RNAs (lncRNAs) that are developmentally regulated and differentially expressed across tissues, suggesting possible roles in cellular differentiation. Despite this expression pattern, little is known about how lncRNAs influence lineage commitment at the molecular level. Here, we reveal that perturbation of an embryonic stem cell (ESC)-specific lncRNA, Pluripotency associated transcript 4 (Platr4), in ESCs directly influences the downstream meso/endoderm differentiation program without affecting pluripotency. We further show that Platr4 interacts with the TEA domain transcription factor 4 (Tead4) to regulate the expression of a downstream target gene crucial in the cardiac lineage program known as connective tissue growth factor (Ctgf). Importantly, Platr4 knockout mice exhibit myocardial atrophy, valve mucinous degenration associated with reduced cardiac output and sudden heart failure. Together, our findings provide evidence that Platr4 expression in undifferentiated ESCs is critical for downstream lineage differentiation, highlighting its importance in disease modeling and regenerative medicine.

scholarly journals Notch Exhibits Ligand Bias and Maneuvers Stage-Specific Steering of Neural Differentiation in Embryonic Stem Cells

2010 ◽  
Vol 30 (8) ◽  
pp. 1946-1957 ◽  
Author(s):  
Saravana Kumar Ramasamy ◽  
Nibedita Lenka
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Differentiation ◽  
Embryonic Stem ◽  
Neural Progenitors ◽  
Stem Cell Maintenance ◽  
Downstream Target ◽  
Downstream Target Gene ◽  
Fate Decision ◽  
Notch Activation

ABSTRACT Notch dictates multiple developmental events, including stem cell maintenance and differentiation, through intercellular communication. However, its temporal influence during early development and, of particular interest, its regulation of binary fate decision at different stages during neurogenesis are among the least explored. Here, using an embryonic stem cell (ESC) model, we have deciphered Notch ligand preference during ESC commitment to different germ layers and determined the stage-specific temporal effect of Notch during neural differentiation. ESCs during maintenance remain impervious to Notch inhibition. However, Notch activation promotes differentiation even in the presence of leukemia inhibitory factor (LIF), displaying ligand preference-associated lineage discrimination, where Jagged-1 favors neural commitment and Delta-like-4 favors the mesoderm. This differential ligand action involves a combination of Notch receptors influencing specific downstream target gene expression. Though Notch activation during early neural differentiation specifically promotes neural stem cells or early neural progenitors and delays their maturation, its inhibition promotes late neural progenitors and expedites neurogenesis, with a preference for neurons over glia. However, gliogenesis is promoted upon Notch activation only when executed in combination with ciliary neurotrophic factor. Thus, our investigation underscores a multifaceted role of Notch, demonstrating the interdependency of ligand usage and lineage specification and Notch acting as a master switch, displaying stage-specific influence on neurogenesis.

The Regulation of Downstream Target Gene AP-2γ by Transcription Factor OCT-4

2013 ◽  
Vol 40 (1) ◽  
pp. 43
Author(s):  
Xiao-Meng ZHAO ◽  
Cheng WANG ◽  
Xiao-Feng LI ◽  
Xiao-Ting ZHANG ◽  
Xi-Zhi LIU ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Gene ◽  
Downstream Target ◽  
Downstream Target Gene

Aryl Hydrocarbon Receptor: Its Regulation and Roles in Transformation and Tumorigenesis

2019 ◽  
Vol 20 (6) ◽  
pp. 625-634 ◽  
Author(s):  
Xun Che ◽  
Wei Dai
Keyword(s):  
Target Gene ◽  
Tumor Development ◽  
Environmental Response ◽  
Carcinogenic Effect ◽  
Post Translational Modifications ◽  
Downstream Target ◽  
Aryl Hydrocarbon ◽  
Downstream Target Gene ◽  
Major Mediator

AhR is an environmental response gene that mediates cellular responses to a variety of xenobiotic compounds that frequently function as AhR ligands. Many AhR ligands are classified as carcinogens or pro-carcinogens. Thus, AhR itself acts as a major mediator of the carcinogenic effect of many xenobiotics in vivo. In this concise review, mechanisms by which AhR trans-activates downstream target gene expression, modulates immune responses, and mediates malignant transformation and tumor development are discussed. Moreover, activation of AhR by post-translational modifications and crosstalk with other transcription factors or signaling pathways are also summarized.

scholarly journals Steroidogenic Factor-1 (SF-1)-Driven Differentiation of Murine Embryonic Stem (ES) Cells into a Gonadal Lineage

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2870-2882 ◽  
Author(s):  
Unmesh Jadhav ◽  
J. Larry Jameson
Keyword(s):  
Target Genes ◽  
De Novo ◽  
Embryoid Body ◽  
Es Cells ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Culture Conditions ◽  
Steroidogenic Factor 1 ◽  
Lineage Differentiation ◽  
And Function

Steroidogenic factor 1 (SF-1) is essential for the development and function of steroidogenic tissues. Stable incorporation of SF-1 into embryonic stem cells (SF-1-ES cells) has been shown to prime the cells for steroidogenesis. When provided with exogenous cholesterol substrate, and after treatment with retinoic acid and cAMP, SF-1-ES cells produce progesterone but do not produce other steroids such as cortisol, estradiol, or testosterone. In this study, we explored culture conditions that optimize SF-1-mediated differentiation of ES cells into defined steroidogenic lineages. When embryoid body formation was used to facilitate cell lineage differentiation, SF-1-ES cells were found to be restricted in their differentiation, with fewer cells entering neuronal pathways and a larger fraction entering the steroidogenic lineage. Among the differentiation protocols tested, leukemia inhibitory factor (LIF) removal, followed by prolonged cAMP treatment was most efficacious for inducing steroidogenesis in SF-1-ES cells. In this protocol, a subset of SF-1-ES cells survives after LIF withdrawal, undergoes morphologic differentiation, and recovers proliferative capacity. These cells are characterized by induction of steroidogenic enzyme genes, use of de novo cholesterol, and production of multiple steroids including estradiol and testosterone. Microarray studies identified additional pathways associated with SF-1 mediated differentiation. Using biotinylated SF-1 in chromatin immunoprecipitation assays, SF-1 was shown to bind directly to multiple target genes, with induction of binding to some targets after steroidogenic treatment. These studies indicate that SF-1 expression, followed by LIF removal and treatment with cAMP drives ES cells into a steroidogenic pathway characteristic of gonadal steroid-producing cells.

Abstract 355: Exercise Prevents Doxorubicin-induced Cardiotoxicity via Targeting Microrna-669a-5p in Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Yihua Bei ◽  
Jiahong Xu ◽  
Tianzhao Xu ◽  
Ping Chen ◽  
Lin Che ◽  
...  
Keyword(s):  
Protective Effect ◽  
Target Gene ◽  
Contractile Function ◽  
Cardiac Contractile Function ◽  
Downstream Target ◽  
Cardiac Contractile ◽  
Downstream Target Gene ◽  
Cardiac Ejection Fraction ◽  
Response To Exercise ◽  
Fractional Shortening

Doxorubicin (Dox)-induced cardiotoxicity, usually associated with increased oxidative stress, myofibrillar deterioration, and impaired cardiac contractile function, is a serious complication of antitumor therapy which may not be detected for many years. Growing evidence indicates that the regulation of cardiac microRNA (miRNA, miR) in response to exercise is essentially involved in the protective effect of exercise in the treatment of cardiovascular diseases. However, it is largely unknown whether and how exercise could prevent Dox-induced cardiotoxicity via regulating miRNA biology. In the current study, C57BL/6 mice were either subjected to a 3-week swimming program or remained sedentary. Mice were then treated with Dox (ip. 4 mg/kg/week for 4 weeks) to induce cardiotoxicity. Our data demonstrated that Dox resulted in marked reduction of cardiac ejection fraction (EF, %) and fractional shortening (FS, %) as measured by echocardiography. Interestingly, exercise significantly improved cardiac EF (%) and FS (%) in Dox-treated mice, indicating the protective effect of exercise in Dox-induced cardiotoxicity. Then, we performed microarray analysis (Affymetrix 3.0) showing that miR-27a-5p, miR-34b-3p, miR-185-3p, miR-203-3p, miR-669a-5p, miR-872-3p, and let-7i-3p were significantly reduced, while miR-2137 was increased in the hearts of exercised Dox-treated mice versus sedentary Dox-treated mice (FC(abs)>1.5, p<0.05). Using qRT-PCR, we further verified that miR-669a-5p was reduced by exercise training in Dox-treated mice. These data reveal that miR-669a-5p might be a potential miRNA mimicking the benefit of exercise in Dox-induced cardiotoxicity. Further study is needed to clarify the functional effect of miR-669a-5p and to identify its downstream target gene that contributes to the prevention and treatment of Dox-induced cardiotoxicity.

scholarly journals Opportunities for Antibody Discovery Using Human Pluripotent Stem Cells: Conservation of Oncofetal Targets

2019 ◽  
Vol 20 (22) ◽  
pp. 5752 ◽  
Author(s):  
Heng Liang Tan ◽  
Andre Choo
Keyword(s):  
Stem Cells ◽  
Cancer Cells ◽  
Pluripotent Stem Cells ◽  
Disease Modeling ◽  
Embryonic Stem ◽  
Oncofetal Antigens ◽  
Antibody Discovery ◽  
Induced Pluripotent ◽  
New Biomarkers

Pluripotent stem cells (PSCs) comprise both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). The application of pluripotent stem cells is divided into four main areas, namely: (i) regenerative therapy, (ii) the study and understanding of developmental biology, (iii) drug screening and toxicology and (iv) disease modeling. In this review, we describe a new opportunity for PSCs, the discovery of new biomarkers and generating antibodies against these biomarkers. PSCs are good sources of immunogen for raising monoclonal antibodies (mAbs) because of the conservation of oncofetal antigens between PSCs and cancer cells. Hence mAbs generated using PSCs can potentially be applied in two different fields. First, these mAbs can be used in regenerative cell therapy to characterize the PSCs. In addition, the mAbs can be used to separate or eliminate contaminating or residual undifferentiated PSCs from the differentiated cell product. This step is critical as undifferentiated PSCs can form teratomas in vivo. The mAbs generated against PSCs can also be used in the field of oncology. Here, novel targets can be identified and the mAbs developed as targeted therapy to kill the cancer cells. Conversely, as new and novel oncofetal biomarkers are discovered on PSCs, cancer mAbs that are already approved by the FDA can be repurposed for regenerative medicine, thus expediting the route to the clinics.

scholarly journals LINC00261 Suppresses Cisplatin Resistance of Esophageal Squamous Cell Carcinoma Through miR-545-3p/MT1M Axis

2021 ◽  
Vol 9 ◽  
Author(s):  
Lijun Wang ◽  
Xiaojun Wang ◽  
Pengwei Yan ◽  
Yatian Liu ◽  
Xuesong Jiang
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Cure Rate ◽  
Downstream Target ◽  
Downstream Target Gene ◽  
Non Coding Rnas ◽  
New Treatment

To improve the survival rate and cure rate of patients, it is necessary to find a new treatment scheme according to the molecular composition of (ESCC) in esophageal squamous cell carcinoma. Long non-coding RNAs (lncRNAs) regulate the progression of ESCC by various pathophysiological pathways. We explored the possible function of the lncRNA LINC00261 (LINC00261) on cisplatin (DDP) resistance of ESCC and its relative molecular mechanisms. In the study, we found that LINC00261 was downregulated in ESCC tissues, cell lines, and DDP-resistant ESCC patients. Besides, overexpression of LINC00261 not only inhibited cell proliferation, and DDP resistance but also promotes cell apoptosis. Further mechanistic research showed that LINC00261 sponged miR-545-3p which was negatively correlated with the expression of LINC00261. In addition, functional experiments revealed that upregulation of miR-766-5p promoted proliferation and enhanced DDP resistance. Subsequently, MT1M was testified to be the downstream target gene of miR-545-3p. Rescue experiments revealed that overexpression of MT1M largely restores miR-545-3p mimics-mediated function on ESCC progression. Our results demonstrate that the LINC00261 suppressed the DDP resistance of ESCC through miR-545-3p/MT1M axis.

scholarly journals Human Bone Marrow Mesenchymal Stromal Cell-Derived Extracellular Vesicles Promote Proliferation of Degenerated Nucleus Pulposus Cells and the Synthesis of Extracellular Matrix Through the SOX4/Wnt/β-Catenin Axis

2021 ◽  
Vol 12 ◽  
Author(s):  
Haoyu Wang ◽  
Fei Li ◽  
Wenrui Ban ◽  
Jing Zhang ◽  
Guiqi Zhang
Keyword(s):  
Extracellular Matrix ◽  
Nucleus Pulposus ◽  
Extracellular Vesicles ◽  
Target Genes ◽  
Intervertebral Disk ◽  
Human Bone ◽  
Nucleus Pulposus Cells ◽  
Synthetic Genes ◽  
Downstream Target ◽  
Transcription Factor 4

Objective: Intervertebral disk degeneration (IDD) is a major cause of pain in the back, neck, and radiculus. Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) are therapeutic in musculoskeletal degenerative diseases such as IDD. This study explored the effect and functional mechanism of human bone MSCs (hBMSCs)-derived EVs in proliferation and apoptosis of degenerated nucleus pulposus cells (DNPCs) and extracellular matrix (ECM) synthesis.Methods: Extracellular vesicles were isolated from hBMSCs and identified. DNPCs were induced by TNF-α. EVs were incubated with DNPCs for 24h. Internalization of EVs by DNPCs, DNPCs proliferation, apoptosis, and expressions of ECM synthetic genes, degrading genes and miR-129-5p were assessed. Downstream target genes of miR-129-5p were predicted. Target relation between miR-129-5p and SRY-box transcription factor 4 (SOX4) was verified. DNPCs proliferation, apoptosis, and ECM synthesis were measured after treatment with EVs and miR-129-5p inhibitor or SOX4 overexpression. Expressions of SOX4 and Wnt/β-catenin pathway-related proteins were determined.Results: hBMSC-EVs promoted DNPCs proliferation, inhibited apoptosis, increased expressions of ECM synthetic genes, and reduced expressions of ECM degrading genes. hBMSC-EVs carried miR-129-5p into DNPCs. Silencing miR-129-5p in EVs partially inverted the effect of EVs on DNPCs proliferation and ECM synthesis. miR-129-5p targeted SOX4. SOX4 overexpression annulled the effect of EVs on DNPCs proliferation and ECM synthesis. Expressions of Wnt1 and β-catenin were decreased in EVs-treated DNPCs, while silencing miR-129-5p in EVs promoted expressions of Wnt1 and β-catenin.Conclusion: hBMSC-EVs promoted DNPCs proliferation and ECM synthesis by carrying miR-129-5p into DNPCs to target SOX4 and deactivating the Wnt/β-catenin axis.

Sign in / Sign up

Export Citation Format

Share Document