Stabilizing heterochromatin by ZKSCAN3 safeguards hMSCs from senescence
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA611555 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11271716_1.fastq.gz | Fastqsanger.gz | |||
| SRR11271716_2.fastq.gz | Fastqsanger.gz | |||
| SRR11271717_1.fastq.gz | Fastqsanger.gz | |||
| SRR11271717_2.fastq.gz | Fastqsanger.gz | |||
| SRR11271718_1.fastq.gz | Fastqsanger.gz |
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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
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
Project description:Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) has long been known as a master transcriptional repressor of autophagy. Here, we identify a novel role for ZKSCAN3 in alleviating senescence that is independent of its autophagy-related activity. Downregulation of ZKSCAN3 is observed in aged human mesenchymal stem cells (hMSCs) and depletion of ZKSCAN3 accelerates senescence of these cells. Mechanistically, ZKSCAN3 maintains heterochromatin stability via interaction with heterochromatin-associated proteins and nuclear lamina proteins. Further study shows that ZKSCAN3 deficiency results in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, loss of heterochromatin, a more accessible chromatin status and consequently, aberrant transcription of repetitive sequences. Overexpression of ZKSCAN3 not only rescues premature senescence phenotypes in ZKSCAN3-deficient hMSCs but also rejuvenates physiologically and pathologically senescent hMSCs. Together, these data reveal for the first time that ZKSCAN3 functions as an epigenetic modulator to maintain heterochromatin organization and thereby attenuate cellular senescence. Our findings establish a new functional link among ZKSCAN3, epigenetic regulation, and stem cell aging.
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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 preventing 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 domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1gamma. Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
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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 preventing 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 domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1g Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
2018-06-30 | GSE116303 | GEO
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 preventing 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 domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1gamma Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
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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 preventing 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 domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1g Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
2019-04-24 | GSE130206 | GEO
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 preventing 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 domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1g expressing of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 expressing alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
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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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