Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Safeguarding nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis

ABSTRACT: Chromobox homolog 4 (CBX4), a component of polycomb repressive complexes 1 (PRC1), plays important roles in the maintenance of cell identity and organism development through epigenetic silencing. However, it remains unclear whether CBX4 regulates the homeostasis of human stem cells. Here, we demonstrate that CBX4 counteracts human mesenchymal stem cell (hMSC) aging via the maintenance of nucleolar homeostasis. CBX4 protein decreases in aged hMSCs, and targeted knockout of CBX4 in young hMSCs destabilizes nucleolar heterochromatin, increases ribosome biogenesis, and accelerates cellular senescence. CBX4 maintains nucleolar homeostasis by recruiting fibrillarin at nucleolar rDNA repeats, limiting excessive expression of rRNAs. Importantly, overexpression of CBX4 expression alleviates physiological hMSC aging as well as attenuates the development of post-traumatic osteoarthritis in mice. Taken together, our study uncovers a novel role of CBX4 in counteracting senescence by maintaining nucleolar homeostasis, providing a potential therapeutic target for aging-associated disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117084 | GEO | 2019/07/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Maintenance of nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis

Project description:CBX4, a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through epigenetic silencing. However, whether CBX4 regulates the homeostasis of human stem cells remains unclear. Here, we demonstrate that CBX4 counteracts human mesenchymal stem cell (hMSC) aging via the maintenance of nucleolar homeostasis. CBX4 protein is decreased in aged hMSCs, and targeted CBX4 knockout in young hMSCs results in destabilized nucleolar heterochromatin, increased ribosome biogenesis and protein translation, and accelerated cellular senescence. CBX4 maintains nucleolar homeostasis by recruiting nucleolar protein fibrillarin and heterochromatin organization associated protein KAP1 at nucleolar rDNA, limiting the excessive expression of rRNAs. Importantly, overexpression of CBX4 alleviates physiological hMSC aging and attenuates the development of posttraumatic osteoarthritis in mice. Taken together, our findings reveal a novel role of CBX4 in counteracting senescence by maintaining nucleolar homeostasis, providing a potential therapeutic target for aging-associated disorders.

2019-01-19 | GSE125320 | GEO

Safeguarding nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis

Project description:Safeguarding nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis

| PRJNA481020 | ENA

Maintenance of nucleolar homeostasis by PC2 alleviates senescence and osteoarthritis

Project description:Polycomb 2 protein (PC2), a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through epigenetic silencing. However, whether PC2 regulates the homeostasis of human stem cells remains unclear. Here, we demonstrate that PC2 counteracts human mesenchymal stem cell (hMSC) aging via the maintenance of nucleolar homeostasis. PC2 protein is decreased in aged hMSCs, and targeted PC2 knockout in young hMSCs results in destabilized nucleolar heterochromatin, increased ribosome biogenesis and protein translation, and accelerated cellular senescence. PC2 maintains nucleolar homeostasis by recruiting nucleolar protein fibrillarin and heterochromatin organization associated protein KAP1 at nucleolar rDNA, limiting the excessive expression of rRNAs. Importantly, overexpression of PC2 alleviates physiological hMSC aging and attenuates the development of posttraumatic osteoarthritis in mice. Taken together, our findings reveal a novel role of PC2 in counteracting senescence by maintaining nucleolar homeostasis, providing a potential therapeutic target for aging-associated disorders.

2018-10-10 | GSE121033 | GEO

Overexpression of Cbx4 wild type and of a Cbx4 sumoylation mutant in human epidermal stem cells

Project description:Human epidermal stem cells transit from a slow cycling to an actively proliferating state to contribute to homeostasis. Both stem cell states differ in their cell cycle profiles but must remain guarded from differentiation and senescence. Here we show that Cbx4, a Polycomb Repressive Complex-1 (PRC1)-associated protein, maintains human epidermal stem cells slow-cycling and undifferentiated, while protecting them from senescence. Interestingly, abrogating the polycomb activity of Cbx4 impairs its anti-senescent function without affecting stem cell differentiation, indicating that differentiation and senescence are independent processes in human epidermis. Conversely, Cbx4 inhibits stem cell activation and differentiation through its SUMO ligase activity. Global transcriptome and chromatin occupancy analyses indicate that Cbx4 regulates modulators of epidermal homeostasis and represses factors, such as Ezh2, Dnmt1, and Bmi1, to prevent the activate stem cell state. Our results suggest that distinct Polycomb complexes balance epidermal stem cell dormancy and activation, while continually preventing senescence and differentiation. Primary human keratinocytes were infected with control vector pBABE, Cbx4 wildtype and a Sumoylation mutant version of Cbx4 (the two Sumo Interaction Motifs were deleted), both fused to a Estrogen Receptor to render their activaty inducible by addition of 4OHT to the media. Cells were cultured for 5 days (after infection and selection) under 4OHT treatment, after which total RNA was collected.

2011-08-01 | E-GEOD-31094 | biostudies-arrayexpress

Maintenance of nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis

Project description:Maintenance of nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis

| PRJNA515848 | ENA

Knockdown and Overexpression of Cbx4 wild type and of a Cbx4 chromodomain mutant in human epidermal stem cells

Project description:Human epidermal stem cells transit from a slow cycling to an actively proliferating state to contribute to homeostasis. Both stem cell states differ in their cell cycle profiles but must remain guarded from differentiation and senescence. Here we show that Cbx4, a Polycomb Repressive Complex-1 (PRC1)-associated protein, maintains human epidermal stem cells slow-cycling and undifferentiated, while protecting them from senescence. Interestingly, abrogating the polycomb activity of Cbx4 impairs its anti-senescent function without affecting stem cell differentiation, indicating that differentiation and senescence are independent processes in human epidermis. Conversely, Cbx4 inhibits stem cell activation and differentiation through its SUMO ligase activity. Global transcriptome and chromatin occupancy analyses indicate that Cbx4 regulates modulators of epidermal homeostasis and represses factors, such as Ezh2, Dnmt1, and Bmi1, to prevent the activate stem cell state. Our results suggest that distinct Polycomb complexes balance epidermal stem cell dormancy and activation, while continually preventing senescence and differentiation. Primary human keratinocytes were infected with control vector pBABE, Cbx4 wildtype and a chromodomain mutant version of Cbx4 (F11A and W35L), both fused to a Estrogen Receptor to render their activaty inducible by addition of 4OHT to the media. Cells were cultured for 5 days (after infection and selection) under 4OHT treatment, after which total RNA was collected. For the knockdown, the pRetroSuperPuro was used as a control vector, in which a shRNA sequence for Cbx4 was introduced to interfere with Cbx4 expression. Cell were cultured in the same way as for the overexpression experiments.

2011-08-01 | E-GEOD-31093 | biostudies-arrayexpress

SIRT7 counteracts mesenchymal stem cell senescence via stabilizing heterochromatin

Project description:Human mesenchymal stem cell (hMSC) senescence contributes to the imbalance of tissue homeostasis during aging. However, the connection between Sirtuin 7 (SIRT7) and hMSC homeostasis remains unclear. Here, we discovered a pivotal role of SIRT7 in protecting hMSC from senescence. We detected a decreased expression of SIRT7 during hMSC aging, while overexpression of which reversed premature hMSC senescence phenotypes. Mechanistically, we proved SIRT7 as a novel interacting protein of the heterochromatin complex, whose deficiency disrupted heterochromatin organization, thereby contributing to the derepression of the retrotransposon Long Interspersed Element 1 (LINE1 or L1). SIRT7-deficient hMSCs accumulated LINE1 in cytoplasm stimulating innate immune response by activated the cyclic GMP-AMP synthase (cGAS) and its downstream signaling effector stimulator of interferon genes (STING). Moreover, reverse-transcriptase inhibitors (RTis), such as Lamivudine (3TC), attenuated these senescence phenotypes of SIRT7-deficient hMSCs. Taken together, our findings identify SIRT7-heterochromatin via LINE1-cGAS/STING influence innate immune response, which contributes more comprehensive understanding of the physiological and function of SIRT7 and help us to find novel targets for the treatment of aging and aging relative diseases.

2020-06-29 | GSE146247 | GEO

Overexpression of Cbx4 wild type and of a Cbx4 sumoylation mutant in human epidermal stem cells

2011-08-02 | GSE31094 | GEO

Knockdown and Overexpression of Cbx4 wild type and of a Cbx4 chromodomain mutant in human epidermal stem cells

2011-08-02 | GSE31093 | GEO

ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells

Project description:Loss of organelle homeostasis is a hallmark of aging. However, it remains elusive how this occurs at transcriptional levels. Here, we report that human mesenchymal stem cell (hMSC) aging is associated with dysfunction of double-membrane organelles and downregulation of transcription factor ATF6. CRISPR/Cas9-mediated inactivation of ATF6 in hMSCs, not in human embryonic stem cells (hESCs), resulted in premature cellular aging, characteristic of loss of endomembrane homeostasis. Comparative transcriptomic analyses in hMSCs identify 145 constitutive and 112 tunicamycin-induced ATF6-regulated genes implicated in different layers of cellular homeostasis regulation. Notably, FOS was identified as one of the constitutive ATF6 responsive genes, downregulation of which contributes to accelerated hMSC senescence. Our study identifies a novel transcriptional program related to homeostatic regulation of membrane organelles, and provides mechanistic insights into aging-associated attrition of human stem cells.

2018-01-11 | GSE102004 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data