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Maintenance of nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE125320 | GEO | 2019/01/19

REPOSITORIES: GEO

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Safeguarding nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis

Project description: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.

2019-07-13 | GSE117084 | GEO

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.

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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.

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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

Safeguarding nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis

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

| PRJNA481020 | 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

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

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Stabilizing Heterochromatin by DGCR8 Alleviates Senescence and Osteoarthritis

Project description:DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and attenuating aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its miRNA-processing activity, which is mediated by its C-terminal domains. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1 Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathologically and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA processing-independent role for DGCR8 in maintaining heterochromatin organization and attenuating senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.

2019-05-28 | PXD013856 | Pride

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

2011-08-02 | GSE31093 | GEO

Stabilizing heterochromatin by ZKSCAN3 safeguards hMSCs from senescence

Project description:Zinc finger protein with KRAB and SCAN domain 3 (ZKSCAN3), a transcriptional repressor, involves in multiple cellular functions. However, the functions of ZKSCAN3 in the homeostatic maintenance of human stem cells remains elusive. Here, we demonstrated that ZKSCAN3 was crucial for preventing human mesenchymal stem cells (hMSCs) from senescence in an autophagy-independent manner. Downregulation of ZKSCAN3 was observed in senescent hMSCs, and depletion of ZKSCAN3 led to premature aging in hMSCs. Further study uncovered that ZKSCAN3 maintained heterochromatin (HC) stability by interacting with heterochromatin associated proteins KAP1 and HP1 as well as nuclear envelope proteins Lamin B1, LBR and Emerin. Deficiency of ZKSCAN3 resulted in detachment of Lamina-associated domains (LADs) from the lamina, loss of heterochromatin and more accessible chromatin status within the heterochromatin and aberrant expression of repetitive sequences. Overexpression of ZKSCAN3, KAP1 or HP1 respectively rescued the senescent phenotypes in ZKSCAN3-/- hMSCs. Notably, reintroduction of ZKSCAN3 protein also retarded the cellular senescence in the replicative senescent hMSCs, as well as the pathological or physiological aging hMSCs. Together, our study reveals a novel, autophagy-independent role of ZKSCAN3 in the maintenance of heterochromatin stability and attenuation of hMSC senescence. Thus, ZKSCAN3 may be a candidate for alleviating human aging-related disorders.

2020-03-13 | GSE146387 | GEO

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