نتائج البحث - "Transcription Factor 7-Like 2 Protein"

1

TCF7L2 lncRNA: a link between bipolar disorder and body mass index through glucocorticoid signaling

المؤلفون: Huanyao Gao, Brandon J. Coombes, Duan Liu, Richard M. Weinshilboum, Daniel C. Kim, Zhenqing Ye, Tamas Ordog, Mark A. Frye, Jeong Heon Lee, Thanh Thanh L. Nguyen, Brenna Sharp, Huaizhi Huang, Liewei Wang, Joanna M. Biernacka

المصدر: Molecular Psychiatry. 26:7454-7464

الوصف: Bipolar disorder (BD) and obesity are highly comorbid. We previously performed a genome-wide association study (GWAS) for BD risk accounting for the effect of body mass index (BMI), which identified a genome-wide significant single-nucleotide polymorphism (SNP) in the gene encoding the transcription factor 7 like 2 (TCF7L2). However, the molecular function of TCF7L2 in the central nervous system (CNS) and its possible role in the BD and BMI interaction remained unclear. In the present study, we demonstrated by studying human induced pluripotent stem cell (hiPSC)-derived astrocytes, cells that highly express TCF7L2 in the CNS, that the BD-BMI GWAS risk SNP is associated with glucocorticoid-dependent repression of the expression of a previously uncharacterized TCF7L2 transcript variant. That transcript is a long non-coding RNA (lncRNA-TCF7L2) that is highly expressed in the CNS but not in peripheral tissues such as the liver and pancreas that are involved in metabolism. In astrocytes, knockdown of the lncRNA-TCF7L2 resulted in decreased expression of the parent gene, TCF7L2, as well as alterations in the expression of a series of genes involved in insulin signaling and diabetes. We also studied the function of TCF7L2 in hiPSC-derived astrocytes by integrating RNA sequencing data after TCF7L2 knockdown with TCF7L2 chromatin-immunoprecipitation sequencing (ChIP-seq) data. Those studies showed that TCF7L2 directly regulated a series of BD risk genes. In summary, these results support the existence of a CNS-based mechanism underlying BD-BMI genetic risk, a mechanism based on a glucocorticoid-dependent expression quantitative trait locus that regulates the expression of a novel TCF7L2 non-coding transcript.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c4ddd61d1c975027ec76dea2023a2267Test
https://doi.org/10.1038/s41380-021-01274-zTest

2

Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif

المؤلفون: Lisheng Chen, Peter E. Burby, Ken M. Cadigan, Aravinda-Bharathi Ramakrishnan

المصدر: Nucleic Acids Research

الوصف: Transcriptional regulation by Wnt signalling is primarily thought to be accomplished by a complex of β-catenin and TCF family transcription factors (TFs). Although numerous studies have suggested that additional TFs play roles in regulating Wnt target genes, their mechanisms of action have not been investigated in detail. We characterised a Wnt-responsive element (WRE) downstream of the Wnt target geneAxin2and found that TCFs and Caudal-related homeodomain (CDX) proteins were required for its activation. Using a new separation-of-function TCF mutant, we found that WRE activity requires the formation of a TCF/CDX complex. Our systematic mutagenesis of this enhancer identified other sequences essential for activation by Wnt signalling, including several copies of a novel CAG DNA motif. Computational and experimental evidence indicates that the TCF/CDX/CAG mode of regulation is prevalent in multiple WREs. Put together, our results demonstrate the complex nature of cis- and trans- interactions required for signal-dependent enhancer activity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::44a2f4217d9b1d3b08418972f8107751Test
http://europepmc.org/articles/PMC8421206Test

3

Wnt Signaling: From Mesenchymal Cell Fate to Lipogenesis and Other Mature Adipocyte Functions

المؤلفون: Devika P. Bagchi, Ormond A. MacDougald

المصدر: Diabetes

الوصف: Wnt signaling is an ancient and evolutionarily conserved pathway with fundamental roles in the development of adipose tissues. Roles of this pathway in mesenchymal stem cell fate determination and differentiation have been extensively studied. Indeed, canonical Wnt signaling is a significant endogenous inhibitor of adipogenesis and promoter of other cell fates, including osteogenesis, chondrogenesis, and myogenesis. However, emerging genetic evidence in both humans and mice suggests central roles for Wnt signaling in body fat distribution, obesity, and metabolic dysfunction. Herein, we highlight recent studies that have begun to unravel the contributions of various Wnt pathway members to critical adipocyte functions, including carbohydrate and lipid metabolism. We further explore compelling evidence of complex and coordinated interactions between adipocytes and other cell types within adipose tissues, including stromal, immune, and endothelial cells. Given the evolutionary conservation and ubiquitous cellular distribution of this pathway, uncovering the contributions of Wnt signaling to cell metabolism has exciting implications for therapeutic intervention in widespread pathologic states, including obesity, diabetes, and cancers.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e501f226a2be4549561e806f9bfa6013Test
https://doi.org/10.2337/dbi20-0015Test

4

Silencing of long noncoding RNA MYLK‐AS1 suppresses nephroblastoma via down‐regulation of CCNE1 through transcription factor TCF7L2

المؤلفون: Dian Li, Yanhong Cui, Xiangliang Tang, Jingqi Zhang, Xiaofeng Gao, Shibo Zhu, Wei Jia

المصدر: Journal of Cellular Physiology. 236:5757-5770

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Adolescent, Physiology, Clinical Biochemistry, Down-Regulation, Mice, Nude, Biology, Wilms Tumor, Transcription Factor 7-Like 2, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Cell Line, Tumor, Cyclin E, Animals, Humans, Gene silencing, Myosin-Light-Chain Kinase, Transcription factor, Cell Proliferation, Oncogene Proteins, Calcium-Binding Proteins, MYLK, Cell Biology, Middle Aged, Cell cycle, Long non-coding RNA, Antisense RNA, Gene Expression Regulation, Neoplastic, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Female, RNA, Long Noncoding, Transcription Factor 7-Like 2 Protein, Chromatin immunoprecipitation

الوصف: Nephroblastoma, a pediatric kidney cancer, caused by pluripotent embryonic renal precursors. Long noncoding RNAs (lncRNAs) are commonly abnormal expressed in many cancers. In the present study, we fousced on one newly discrovered lncRNA, MYLK Antisense RNA 1 (MYLK-AS1), and its functional role in proliferation and cycle distribution of nephroblastoma cells. Micorarray-based analysis revealed the highly expressed Cyclin E1 (CCNE1) and MYLK-AS1 in nephroblastoma. After nephroblastoma tissue sample collection, RT-qPCR confirmed the upregulated expression of MYLK-AS1 and CCNE1 in nephroblastoma tissues and cells. Kaplan-Meier curve exhibited that patients with elevated CCNE1 had lower overall survival rate in follow-up study. RNA binding protein immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter gene assay were employed to determine the relationship among MYLK-AS1, TCF7L2, and CCNE1, which validated that transcription factor 7-like 2 (TCF7L2) could specifically bind to MYLK-AS1 and TCF7L2 could positively promote CCNE1. After gain- and loss-of function assays, the conclusion that silencing of MYLK-AS1 could inhibit expression of CCNE1 through the transcription factor TCF7L2 to regulate the cell proliferation and cell cycle distribution of nephroblastoma cells was obtained. Subsequently, the subcutaneous tumor formation ability of nephroblastoma cell in nude mice was observed and the silencing of MYLK-AS1 exerts suppressive role in the tumorigenic ability of nephroblastoma cells in vivo. Taken together, MYLK-AS1 constitutes a promising biomarker for the early detection and treatment of nephroblastoma.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::830ee439a292da1d5a5428be76e4b0adTest
https://doi.org/10.1002/jcp.30259Test

5

VBP1 modulates Wnt/β-catenin signaling by mediating the stability of the transcription factors TCF/LEFs

المؤلفون: Caixia Wang, Haifeng Zhang, Ling Lu, Yunzhang Liu, Yun Li, Xiaozhi Rong, Jianfeng Zhou, Chengtian Zhao

المصدر: The Journal of Biological Chemistry

مصطلحات موضوعية: 0301 basic medicine, Transcriptional Activation, animal structures, Embryo, Nonmammalian, Transcription Factor 7-Like 1 Protein, Biochemistry, TCF/LEF, Cell Line, 03 medical and health sciences, Animals, Humans, Phosphorylation, RNA, Small Interfering, Enhancer, Molecular Biology, Zebrafish, Transcription factor, Wnt Signaling Pathway, transcription factor, beta Catenin, Cell Proliferation, Gene knockdown, T-cell factor (TCF), 030102 biochemistry & molecular biology, biology, Chemistry, Effector, Binding protein, Wnt signaling pathway, Cell Biology, Zebrafish Proteins, biology.organism_classification, VBP1, Wnt signaling, Cell biology, Wnt Proteins, Cytoskeletal Proteins, 030104 developmental biology, pVHL, embryonic structures, RNA Interference, Signal transduction, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Signal Transduction, Wnt/β-catenin signaling, Molecular Chaperones

الوصف: The Wnt/β-catenin pathway is one of the major pathways that regulates embryonic development, adult homeostasis, and stem cell self-renewal. In this pathway, transcription factors T-cell factor and lymphoid enhancer factor (TCF/LEF) serve as a key switch to repress or activate Wnt target gene transcription by recruiting repressor molecules or interacting with the β-catenin effector, respectively. It has become evident that the protein stability of the TCF/LEF family members may play a critical role in controlling the activity of the Wnt/β-catenin signaling pathway. However, factors that regulate the stability of TCF/LEFs remain largely unknown. Here, we report that pVHL binding protein 1 (VBP1) regulates the Wnt/β-catenin signaling pathway by controlling the stability of TCF/LEFs. Surprisingly, we found that either overexpression or knockdown of VBP1 decreased Wnt/β-catenin signaling activity in both cultured cells and zebrafish embryos. Mechanistically, VBP1 directly binds to all four TCF/LEF family members and von Hippel-Lindau tumor-suppressor protein (pVHL). Either overexpression or knockdown of VBP1 increases the association between TCF/LEFs and pVHL and then decreases the protein levels of TCF/LEFs via proteasomal degradation. Together, our results provide mechanistic insights into the roles of VBP1 in controlling TCF/LEFs protein stability and regulating Wnt/β-catenin signaling pathway activity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::472bf8b4246de338708d83229b880bf0Test
http://europepmc.org/articles/PMC7864075Test

6

Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation

المؤلفون: Chen Weng, Yan Li, Konstantin Leskov, Fulai Jin, Sisi Lai, Luxin Ke, Anniya Gu, Jian Cui, Haiyan Li, Jiajia Xi

المصدر: Nature metabolism

الوصف: The in vitro differentiation of insulin-producing beta-like cells can model aspects of human pancreatic development. Here, we generate 95,308 single-cell transcriptomes and reconstruct a lineage tree of the entire differentiation process from human embryonic stem cells to beta-like cells to study temporally regulated genes during differentiation. We identify so-called 'switch genes' at the branch point of endocrine/non-endocrine cell fate choice, revealing insights into the mechanisms of differentiation-promoting reagents, such as NOTCH and ROCKII inhibitors, and providing improved differentiation protocols. Over 20% of all detectable genes are activated multiple times during differentiation, even though their enhancer activation is usually unimodal, indicating extensive gene reuse driven by different enhancers. We also identify a stage-specific enhancer at the TCF7L2 locus for diabetes, uncovered by genome-wide association studies, that drives a transient wave of gene expression in pancreatic progenitors. Finally, we develop a web app to visualize gene expression on the lineage tree, providing a comprehensive single-cell data resource for researchers studying islet biology and diabetes.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4fbf12a2b485d3f50c94b6c0ebfaef7eTest
https://doi.org/10.1038/s42255-020-00314Test-2

7

Narrow H3K4me2 is required for chicken PGC formation

المؤلفون: Qi Xu, Qisheng Zuo, Sun Hongyan, Chen Zhang, Jing Jin, Tingting Li, Yuan Xia, Jiuzhou Song, Ming Zhang, Jiancheng Li, Nana He, Guohong Chen, Yang Zhang, Hao Chen, Hao Bai, Guobin Chang, Yani Zhang, Man Wang, Jiang Jingyi, Hengmi Cui, Shi Xiang, Bichun Li

المصدر: Journal of Cellular Physiology. 236:1391-1400

مصطلحات موضوعية: Male, 0301 basic medicine, endocrine system, Physiology, Clinical Biochemistry, Bone Morphogenetic Protein 4, Biology, Wnt-5a Protein, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Transforming Growth Factor beta, Testis, Histone methylation, Animals, Blastoderm, Genitalia, Epigenetics, Gene, Embryonic Stem Cells, Adult Germline Stem Cells, urogenital system, Wnt signaling pathway, Gene Expression Regulation, Developmental, Cell Differentiation, Cell Biology, Embryonic stem cell, Cell biology, WNT5A, Germ Cells, 030104 developmental biology, 030220 oncology & carcinogenesis, embryonic structures, Histone Methyltransferases, Stem cell, Chickens, Transcription Factor 7-Like 2 Protein, Signal Transduction

الوصف: The development of primordial germ cells (PGCs) undergoes epigenetic modifications. The study of histone methylation in regulating PGCs is beneficial to understand the development and differentiation mechanism of germ stem cells. Notably, it provides a theoretical basis for directed induction and mass acquisition in vitro. However, little is known about the regulation of PGC formation by histone methylation. Here, we found the high enrichment of H3K4me2 in the blastoderm, genital ridges, and testis. Chromatin immunoprecipitation sequencing was performed and the results revealed that genomic H3K4me2 is dynamic in embryonic stem cells, PGCs, and spermatogonial stem cells. This trend was consistent with the H3K4me2 enrichment in the gene promoter region. Additionally, narrow region triggered PGC-related genes (Bmp4, Wnt5a, and Tcf7l2) and signaling pathways (Wnt and transforming growth factor-β). After knocking down histone methylase Mll2 in vitro and vivo, the level of H3K4me2 decreased, inhibiting Cvh and Blimp1 expression, then repressing the formation of PGCs. Taken together, our study revealed the whole genome map of H3K4me2 in the formation of PGCs, contributing to improve the epigenetic study in PGC formation and providing materials for bird gene editing and rescue of endangered birds.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9c495898b64811b65120be1695d67b84Test
https://doi.org/10.1002/jcp.29945Test

8

MicroRNA-22-3p targeted regulating transcription factor 7-like 2 (TCF7L2) constrains the Wnt/β-catenin pathway and malignant behavior in osteosarcoma

المؤلفون: XiangQi Meng, Ya Guo, Yanping Jian, Zexiang Deng, Hongwei Cai, YuanLiang Xue, Ning Liu

المصدر: Bioengineered, Vol 0, Iss 0 (2021)

الوصف: Various studies have manifested that microRNAs (miRNAs) are involved in the modulation of the occurrence and development of osteosarcoma (OS). However, whether miR-22-3p is associated with OS growth remains unclear. In the study, the potential molecular mechanisms of miR-22-3p in OS was explored. It was affirmed that miR-22-3p was associated with distant metastasis and tumor size in OS patients, and reduced in OS tissues and cells while transcription factor 7-like 2 (TCF7L2) was elevated. Elevated miR-22-3p repressed OS cell progression, and the Wnt/β-catenin pathway, while elevated TCF7L2 was opposite. MiR-22-3p targeted TCF7L2 in OS. In functional rescue experiments, knockdown of miR-22-3p on OS progression and promotion of Wnt/β-catenin were reversed by simultaneous knockdown of TCF7L2. Transplantation experiments in nude mice showed that elevated miR-22-3p repressed OS tumor growth and decreased TCF7L2, Wnt and β-catenin. Shortly, this study suggest that miR-22-3p refrains the Wnt/β-catenin pathway by targeting TCF7L2 and thereby preventing OS deterioration. MiR-22-3p/TCF7L2 axis is supposed to be a candidate molecular target for future OS treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::240c67ab039509a85e0b9c64373e4b2cTest
https://doaj.org/article/e637dfe03a4c40dc8538721a470a6000Test

9

The Roles of the Colon Cancer Associated Transcript 2 (CCAT2) Long Non-Coding RNA in Cancer: A Comprehensive Characterization of the Tumorigenic and Molecular Functions

المؤلفون: Andreea Nutu, Rares Drula, Ioana Berindan-Neagoe, George A. Calin, Radu Pirlog

المصدر: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 22, Iss 12491, p 12491 (2021)

الوصف: Colon cancer-associated transcript 2 (CCAT2) is an intensively studied lncRNA with important regulatory roles in cancer. As such, cumulative studies indicate that CCAT2 displays a high functional versatility due to its direct interaction with multiple RNA binding proteins, transcription factors, and other species of non-coding RNA, especially microRNA. The definitory mechanisms of CCAT2 are its role as a regulator of the TCF7L2 transcription factor, enhancer of MYC expression, and activator of the WNT/β-catenin pathway, as well as a role in promoting and maintaining chromosome instability through the BOP1–AURKB pathway. Additionally, we highlight how the encompassing rs6983267 SNP has been shown to confer CCAT2 with allele-specific functional and structural particularities, such as the allelic-specific reprogramming of glutamine metabolism. Additionally, we emphasize CCAT2’s role as a competitive endogenous RNA (ceRNA) for multiple tumor suppressor miRNAs, such as miR-4496, miR-493, miR-424, miR-216b, miR-23b, miR-34a, miR-145, miR-200b, and miR-143 and the pro-tumorigenic role of the altered regulatory axis. Additionally, due to its upregulation in tumor tissues, wide distribution across cancer types, and presence in serum samples, we outline CCAT2’s potential as a biomarker and disease indicator and its implications for the development of resistance against current cancer therapy regiments and metastasis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ddc5a0204442f805e3b24fca67d3dfc8Test
http://europepmc.org/articles/PMC8620102Test

10

The heparan sulfate proteoglycan syndecan‐1 regulates colon cancer stem cell function via a focal adhesion kinase—Wnt signaling axis

المؤلفون: Valeria Tria, Rolland Reinbold, George W. Yip, Wey-Cheng Sim, Sherif Abdelaziz Ibrahim, Ileana Zucchi, Burkhard Greve, Sampath Kumar Katakam, Theodoros Karnavas, Martin Götte, Stefano Molgora, Paride Pelucchi, Eleonora Piscitelli, Eslam A. El-Ghonaimy

المصدر: The FEBS Journal
The FEBS journal
(2020). doi:10.1111/febs.15356
info:cnr-pdr/source/autori:Katakam, Sampath Kumar; Tria, Valeria; Sim, Wey-Cheng; Yip, George W.; Molgora, Stefano; Karnavas, Theodoros; Elghonaimy, Eslam A.; Pelucchi, Paride; Piscitelli, Eleonora; Ibrahim, Sherif Abdelaziz; Zucchi, Ileana; Reinbold, Rolland; Greve, Burkhard; Goette, Martin/titolo:The heparan sulfate proteoglycan syndecan-1 regulates colon cancer stem cell function via a focal adhesion kinase-Wnt signaling axis/doi:10.1111%2Ffebs.15356/rivista:The FEBS journal (Print)/anno:2020/pagina_da:/pagina_a:/intervallo_pagine:/volume

مصطلحات موضوعية: 0301 basic medicine, Indoles, Biochemistry, Receptors, G-Protein-Coupled, Syndecan 1, Mice, 0302 clinical medicine, Cell Movement, AC133 Antigen, RNA, Small Interfering, Wnt Signaling Pathway, Sulfonamides, biology, Chemistry, Integrin beta1, Wnt signaling pathway, LGR5, Nanog Homeobox Protein, Epithelial Cell Adhesion Molecule, Tumor Burden, 3. Good health, Cell biology, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Colonic Neoplasms, Neoplastic Stem Cells, Stem cell, HT29 Cells, Oligopeptides, Transcription Factor 7-Like 2 Protein, Homeobox protein NANOG, extracellular matrix, Integrin, Kruppel-Like Transcription Factors, tumor-initiating cells, Aldehyde Dehydrogenase 1 Family, Focal adhesion, 03 medical and health sciences, Cancer stem cell, Spheroids, Cellular, glycosaminoglycan, Animals, Humans, Benzothiazoles, xenograft, Molecular Biology, Cell Proliferation, Cell Biology, syndecans, Xenograft Model Antitumor Assays, Sex-Determining Region Y Protein, 030104 developmental biology, Focal Adhesion Kinase 1, biology.protein, Syndecan-1, Caco-2 Cells

الوصف: In colon cancer, downregulation of the transmembrane heparan sulfate proteoglycan syndecan-1 (Sdc-1) is associated with increased invasiveness, metastasis, and dedifferentiation. As Sdc-1 modulates signaling pathways relevant to stem cell function, we tested the hypothesis that it may regulate a tumor-initiating cell phenotype. Sdc-1 small-interfering RNA knockdown in the human colon cancer cell lines Caco2 and HT-29 resulted in an increased side population (SP), enhanced aldehyde dehydrogenase 1 activity, and higher expression of CD133, LGR5, EPCAM, NANOG, SRY (sex-determining region Y)-box 2, KLF2, and TCF4/TCF7L2. Sdc-1 knockdown enhanced sphere formation, cell viability, Matrigel invasiveness, and epithelial-to-mesenchymal transition-related gene expression. Sdc-1-depleted HT-29 xenograft growth was increased compared to controls. Decreased Sdc-1 expression was associated with an increased activation of β1-integrins, focal adhesion kinase (FAK), and wingless-type (Wnt) signaling. Pharmacological FAK and Wnt inhibition blocked the enhanced stem cell phenotype and invasive growth. Sequential flow cytometric SP enrichment substantially enhanced the stem cell phenotype of Sdc-1-depleted cells, which showed increased resistance to doxorubicin chemotherapy and irradiation. In conclusion, Sdc-1 depletion cooperatively enhances activation of integrins and FAK, which then generates signals for increased invasiveness and cancer stem cell properties. Our findings may provide a novel concept to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence. DATABASES: The GEO accession number of the Affymetrix transcriptomic screening is GSE58751.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c8ea4b24fab851ea7f018baf542f61c0Test
https://doi.org/10.1111/febs.15356Test

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