Stress-activated miR-204 governs senescent phenotypes of chondrocytes to promote osteoarthritis development

2019 ◽  
Vol 11 (486) ◽  
pp. eaar6659 ◽  
Author(s):  
Donghyun Kang ◽  
Jungkwon Shin ◽  
Yongsik Cho ◽  
Hyeon-Seop Kim ◽  
Young-Ran Gu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Ectopic Expression ◽  
Cartilage Matrix ◽  
Cartilage Loss ◽  
Biosynthesis Pathway ◽  
Cellular Event ◽  
Multiple Components ◽  
Progressive Loss ◽  
Secretory Phenotype ◽  
Matrix Metabolism

A progressive loss of cartilage matrix leads to the development of osteoarthritis (OA). Matrix homeostasis is disturbed in OA cartilage as the result of reduced production of cartilage-specific matrix and increased secretion of catabolic mediators by chondrocytes. Chondrocyte senescence is a crucial cellular event contributing to such imbalance in matrix metabolism during OA development. Here, we identify miR-204 as a markedly up-regulated microRNA in OA cartilage. miR-204 is induced by transcription factors GATA4 and NF-κB in response to senescence signals. Up-regulated miR-204 simultaneously targets multiple components of the sulfated proteoglycan (PG) biosynthesis pathway, effectively shutting down PG anabolism. Ectopic expression of miR-204 in joints triggers spontaneous cartilage loss and OA development, whereas miR-204 inhibition ameliorates experimental OA, with concomitant recovery of PG synthesis and suppression of inflammatory senescence-associated secretory phenotype (SASP) factors in cartilage. Collectively, we unravel a stress-activated senescence pathway that underlies disrupted matrix homeostasis in OA cartilage.

scholarly journals OP0202 STRESS-ACTIVATED MIR-204 GOVERNS SENESCENT PHENOTYPES OF CHONDROCYTES TO PROMOTE OSTEOARTHRITIS DEVELOPMENT

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 126.3-126
Author(s):  
Y. Cho ◽  
D. Kang ◽  
J. H. Kim
Keyword(s):  
Ectopic Expression ◽  
Cartilage Degeneration ◽  
Cartilage Destruction ◽  
Knee Joints ◽  
Multiple Components ◽  
Post Traumatic ◽  
Matrix Metabolism ◽  
In Vivo Effects ◽  
Surgically Induced

Background:A progressive loss of cartilage matrix leads to the development of osteoarthritis (OA). Matrix homeostasis is disturbed in OA cartilage as the result of reduced production of cartilage-specific matrix and increased secretion of catabolic mediators by chondrocytes. Chondrocyte senescence is a crucial cellular event contributing to such imbalance in matrix metabolism during OA development.Objectives:We sought to identify a previously unknown, senescence-associated signaling pathway in chondrocytes linked to major OA cartilage manifestations such as PG loss and cartilage degeneration.Methods:We particularly aimed to screen miRNAs whose inhibition could effectively modulate senescent phenotypes of chondrocytes to treat OA. We investigated the regulatory mechanisms of miR-204 under various stress-eliciting stimuli in primary cultured human and mouse chondrocytes. We examined the in vivo effects of miR-204 overexpression and its antagonism in surgically induced OA mouse models. DMM surgery was used to induce posttraumatic OA in 12-week-old mice. Small RNAs were delivered to mouse knee joints by intra-articular injection. Various OA manifestations including cartilage destruction, subchondral bone sclerosis, osteophyte maturity, and synovial inflammation in mice were histologically inspected.Results:We identify miR-204 as a senescence-associated microRNA (miRNA) which is markedly upregulated in OA cartilage. The upregulated miR-204 simultaneously targets multiple components of the sulfated proteoglycan (PG) biosynthesis pathway, effectively shutting down PG anabolism. Ectopic expression of the miR-204 in joints triggers spontaneous cartilage loss and OA development, whereas inhibition of miR-204 ameliorates experimental OA, with concomitant recovery of PG synthesis and suppression of inflammatory senescence-associated secretory phenotype (SASP) factors in cartilageConclusion:we unravel a stress-activated senescence pathway that underlies disrupted matrix homeostasis in OA cartilage.References:[1]O. H. Jeon, C. Kim, R.-M. Laberge, M. Demaria, S. Rathod, A. P. Vasserot, J. W. Chung, D. H. Kim, Y. Poon, N. David, D. J. Baker, J. M. van Deursen, J. Campisi, J. H. Elisseeff, Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017)Disclosure of Interests:None declared

scholarly journals Biological importance of OCT transcription factors in reprogramming and development

2021 ◽  
Author(s):  
Kee-Pyo Kim ◽  
Dong Wook Han ◽  
Johnny Kim ◽  
Hans R. Schöler
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Ectopic Expression ◽  
Donor Cell ◽  
Structural Components ◽  
Oct4 Expression ◽  
Reprogramming Factors ◽  
Induced Pluripotent

AbstractEctopic expression of Oct4, Sox2, Klf4 and c-Myc can reprogram somatic cells into induced pluripotent stem cells (iPSCs). Attempts to identify genes or chemicals that can functionally replace each of these four reprogramming factors have revealed that exogenous Oct4 is not necessary for reprogramming under certain conditions or in the presence of alternative factors that can regulate endogenous Oct4 expression. For example, polycistronic expression of Sox2, Klf4 and c-Myc can elicit reprogramming by activating endogenous Oct4 expression indirectly. Experiments in which the reprogramming competence of all other Oct family members tested and also in different species have led to the decisive conclusion that Oct proteins display different reprogramming competences and species-dependent reprogramming activity despite their profound sequence conservation. We discuss the roles of the structural components of Oct proteins in reprogramming and how donor cell epigenomes endow Oct proteins with different reprogramming competences.

scholarly journals Msn2- and Msn4-Like Transcription Factors Play No Obvious Roles in the Stress Responses of the Fungal Pathogen Candida albicans

2004 ◽  
Vol 3 (5) ◽  
pp. 1111-1123 ◽  
Author(s):  
Susan Nicholls ◽  
Melissa Straffon ◽  
Brice Enjalbert ◽  
André Nantel ◽  
Susan Macaskill ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Transcription Factors ◽  
Stress Responses ◽  
Ectopic Expression ◽  
Heavy Metal Stress ◽  
Luciferase Reporter ◽  
Response Element ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Adverse Environmental Conditions

ABSTRACT In Saccharomyces cerevisiae, the (C2H2)2 zinc finger transcription factors Msn2 and Msn4 play central roles in responses to a range of stresses by activating gene transcription via the stress response element (STRE; CCCCT). The pathogen Candida albicans displays stress responses that are thought to help it survive adverse environmental conditions encountered within its human host. However, these responses differ from those in S. cerevisiae, and hence we predicted that the roles of Msn2- and Msn4-like proteins might have been functionally reassigned in C. albicans. C. albicans has two such proteins: CaMsn4 and Mnl1 (for Msn2- and Msn4-like). CaMSN4, but not MNL1, weakly complemented the inability of an S. cerevisiae msn2 msn4 mutant to activate a STRE-lacZ reporter. Also, the disruption of CaMsn4 and Mnl1 had no discernible effect upon the resistance of C. albicans to heat, osmotic, ethanol, nutrient, oxidative, or heavy-metal stress or upon the stress-activated transcriptome in C. albicans. Furthermore, although Cap1-dependent activation of a Yap response element-luciferase reporter was observed, a STRE reporter was not activated in response to stresses in C. albicans. Ectopic expression of CaMsn4 or Mnl1 did not affect the cellular or molecular responses of C. albicans to stress. Under the conditions tested, the putative activation and DNA binding domains of CaMsn4 did not appear to be functional. These data suggest that CaMsn4 and Mnl1 do not contribute significantly to stress responses in C. albicans. The data are consistent with the idea that stress signaling in this fungus has diverged significantly from that in budding yeast.

scholarly journals The Sp transcription factors are involved in the cellular expression of the human glucose-dependent insulinotropic polypeptide receptor gene and overexpressed in adrenals of patients with Cushing’s syndrome

2005 ◽  
Vol 35 (1) ◽  
pp. 61-71 ◽  
Author(s):  
Valérie Baldacchino ◽  
Sylvie Oble ◽  
Patrick-Olivier Décarie ◽  
Isabelle Bourdeau ◽  
Pavel Hamet ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cushing’S Syndrome ◽  
Receptor Gene ◽  
Gene Array ◽  
Ectopic Expression ◽  
Cushing's Syndrome ◽  
Tissue Array ◽  
R Gene ◽  
Consensus Sequences ◽  
Cellular Expression

The best characterized effect of glucose-dependent insulinotropic polypeptide (GIP) is its stimulatory effect on insulin secretion by pancreatic β-cells. Recently, it was demonstrated that some cases of primary adrenal Cushing’s syndrome were secondary to the ectopic expression of non-mutated GIP receptor (GIP-R) in bilateral adrenal hyperplasias or unilateral adrenal adenomas, resulting in food-dependent steroidogenesis. Using a human multiple-expression tissue array, GIP-R was found to be expressed in a large number of human adult and fetal tissues, but not in the adrenal gland. The analysis of the promoter region of human (h) GIP-R gene revealed six consensus sequences important in regulating the reporter gene activity and capable of binding to Sp1 and Sp3 transcription factors. Data obtained by gene array and semi-quantitative RT-PCR showed an increase in the expression of Sp3 and CRSP9 (co-regulator of Sp1 transcription factor, subunit 9) in the adrenal adenomas or bilateral macronodular hyperplasias of patients with GIP-dependent Cushing’s syndrome; they were, however, also increased in some patients with non-GIP-dependent cortisol-secreting adenomas or with ACTH-dependent Cushing’s disease. This study represents the first step in our understanding of the mechanisms involved in the regulation of the expression of the hGIP-R gene.

scholarly journals A mini review on production of pluripotency factors (Oct4, Sox2, Klf4 and c-Myc) through recombinant protein technology

2020 ◽  
Vol 5 (1) ◽  
pp. 1-4 ◽  
Author(s):  
David Septian Sumanto Marpaung ◽  
Ayu Oshin Yap Sinaga
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Embryonic Stem Cells ◽  
Pluripotent Stem Cells ◽  
Ectopic Expression ◽  
Embryonic Stem ◽  
Cell Types ◽  
Induced Pluripotency ◽  
Pluripotency Factors ◽  
Induced Pluripotent

The four transcription factors OCT4, SOX2, KLF4 and c-MYC are highly expressed in embryonic stem cells (ESC) and their overexpression can induce pluripotency, the ability to differentiate into all cell types of an organism. The ectopic expression such transcription factors could reprogram somatic stem cells become induced pluripotency stem cells (iPSC), an embryonic stem cells-like. Production of recombinant pluripotency factors gain interests due to high demand from generation of induced pluripotent stem cells in regenerative medical therapy recently. This review will focus on demonstrate the recent advances in recombinant pluripotency factor production using various host.

scholarly journals Cooperation between HNF-1α, Cdx2, and GATA-4 in initiating an enterocytic differentiation program in a normal human intestinal epithelial progenitor cell line

2010 ◽  
Vol 298 (4) ◽  
pp. G504-G517 ◽  
Author(s):  
Yannick D. Benoit ◽  
Fréderic Paré ◽  
Caroline Francoeur ◽  
Dominique Jean ◽  
Eric Tremblay ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Line ◽  
Large Scale ◽  
Morphological Changes ◽  
Ectopic Expression ◽  
Functional Differentiation ◽  
Stem Cell Markers ◽  
Intestinal Epithelial ◽  
Differentiation Markers ◽  
Functional Features

In the intestinal epithelium, the Cdx, GATA, and HNF transcription factor families are responsible for the expression of differentiation markers such as sucrase-isomaltase. Although previous studies have shown that Cdx2 can induce differentiation in rat intestinal IEC-6 cells, no data are available concerning the direct implication of transcription factors on differentiation in human normal intestinal epithelial cell types. We investigated the role of Cdx2, GATA-4, and HNF-1α using the undifferentiated human intestinal epithelial crypt cell line HIEC. These transcription factors were tested on proliferation and expression of polarization and differentiation markers. Ectopic expression of Cdx2 or HNF-1α, alone or in combination, altered cell proliferation abilities through the regulation of cyclin D1 and p27 expression. HNF-1α and GATA-4 together induced morphological modifications of the cells toward polarization, resulting in the appearance of functional features such as microvilli. HNF-1α was also sufficient to induce the expression of cadherins and dipeptidylpeptidase, whereas in combination with Cdx2 it allowed the expression of the late differentiation marker sucrase-isomaltase. Large-scale analysis of gene expression confirmed the cooperative effect of these factors. Finally, although DcamKL1 and Musashi-1 expression were downregulated in differentiated HIEC, other intestinal stem cell markers, such as Bmi1, were unaffected. These observations show that, in cooperation with Cdx2, HNF-1α acts as a key factor on human intestinal cells to trigger the onset of their functional differentiation program whereas GATA-4 appears to promote morphological changes.

scholarly journals Genome-wide study of pineapple (Ananas comosus L.) bHLH transcription factors indicates that cryptochrome-interacting bHLH2 (AcCIB2) participates in flowering time regulation and abiotic stress response

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Mohammad Aslam ◽  
Bello Hassan Jakada ◽  
Beenish Fakher ◽  
Joseph G. Greaves ◽  
Xiaoping Niu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Abiotic Stress ◽  
Stress Response ◽  
Flowering Time ◽  
Current Knowledge ◽  
Ectopic Expression ◽  
Ananas Comosus ◽  
Biological Processes ◽  
Abiotic Stress Response ◽  
Bhlh Genes

Abstract Background Transcription factors (TFs) are essential regulators of growth and development in eukaryotes. Basic-helix-loop-helix (bHLHs) is one of the most significant TFs families involved in several critical regulatory functions. Cryptochrome-interacting bHLH (CIB) and cryptochromes form an extensive regulatory network to mediate a plethora of pathways. Although bHLHs regulate critical biological processes in plants, the information about pineapple bHLHs remains unexplored. Results Here, we identified a total of 121 bHLH proteins in the pineapple genome. The identified genes were renamed based on the ascending order of their gene ID and classified into 18 subgroups by phylogenetic analysis. We found that bHLH genes are expressed in different organs and stages of pineapple development. Furthermore, by the ectopic expression of AcCIB2 in Arabidopsis and complementation of Atcib2 mutant, we verified the involvement of AcCIB2 in photomorphogenesis and abiotic stress response. Conclusions Our findings revealed that AcCIB2 plays an essential role in flowering time regulation and abiotic stress response. The present study provides additional insights into the current knowledge of bHLH genes and suggests their potential role in various biological processes during pineapple development.

46 EXPRESSION OF TRANSCRIPTION FACTORS SPECIFIC TO THE TROPHOBLAST LINEAGE IN MOUSE SOMATIC NUCLEAR TRANSFER EMBRYOS

2008 ◽  
Vol 20 (1) ◽  
pp. 103
Author(s):  
T. Mitani ◽  
M. Nishiwaki ◽  
M. Anzai ◽  
H. Kato ◽  
Y. Hosoi ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Real Time ◽  
Real Time Pcr ◽  
Nuclear Transfer ◽  
Ectopic Expression ◽  
Expression Level ◽  
Pcr Analysis ◽  
Cell Stage ◽  
Cdx2 Expression ◽  
Morula Stage

Somatic cell nuclear transfer (SCNT) embryos can develop at relatively high rates during the preimplantation period; however, most of these fail after implantation. Development of extraembryonic tissue is indispensable for normal embryonic development. Hence, an abnormality of trophoblast development might be a significant factor in post-implantation lethality of SCNT embryos. A transcription factor, caudal-related homeobox 2 (Cdx2), appears to be involved in the segregation of ICM and trophectoderm (TE) in preimplantation embryos (Niwa et al. 2005 Cell 123, 917–929). Both Cdx2 and Oct3/4 are expressed in all cells at the morula stage, and then Cdx2 expression becomes restricted to the TE and Oct3/4 to the ICM as the blastocyst develops. Mouse embryos deficient in Cdx2 are able to develop to normal blastocysts but die soon after implantation, probably because of defects in the TE lineage. Moreover, dysplasia of the spongiotrophoblast layer might attribute to an abnormality of Tpbpa expression in mouse SCNT embryos (Wakisaka-Saito et al. 2006 Biochem. Biophys. Res. Commun. 349, 106–114). In this study, we examined the expression profiles of transcription factors implicated in trophoblast development in mouse SCNT embryos and intracytoplasmic sperm injection (ICSI) embryos by immunohistochemistry and real-time PCR analysis. SCNT embryos were produced according to the method reported previously (Wakayama et al. 1998 Nature 394, 369–374). In brief, B6D2F1 and B6C3F1 female mice were used for the collection of recipient oocytes and donor cells, respectively. After nuclear transfer, the oocytes were activated and cultured in KSOM to the morula and blastocyst stages. Immunohistochemical analysis demonstrated that in ICSI embryos Cdx2 was only partially expressed at the 8-cell stage but completely in early morulae. In contrast, in SCNT embryos, it was absent at the 8-cell stage and appeared partially at the early morula stage. Thereafter, Cdx2 expression became restricted to the TE cells in both the ICSI and the SCNT blastocysts. However, ectopic expression of Oct3/4 was observed in the TE cells of SCNT, but not in ICSI blastocysts. Real-time PCR analysis showed that at the 8-cell stage, Cdx2 was expressed in ICSI but not in SCNT embryos. In addition, the expression level of Cdx2 in SCNT embryos at the blastocyst stage was only half that in ICSI embryos (P < 0.05). However, there was no significant difference in expression level of Oct3/4 between ICSI and SCNT embryos. Eomesodermin (Eomes) is also implicated in trophoblast development and its expression depends on Cdx2, BMP4, and FGF4. In SCNT embryos, the expression level of Eomes was also only half that in ICSI embryos. These results indicate that the delayed expression of Cdx2 in SCNT embryos may lead to the ectopic expression of Oct3/4 in blastocysts and, along with the limited expression of Cdx2 and Eomes, may contribute to disorders in the function of the trophoblast lineage for normal placental development. This work was supported by a Grant-in-Aid for the 21st Century Center of Excellence Program of the MEXT, Japan, and by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.

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