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SIRT7 counteracts mesenchymal stem cell senescence via stabilizing heterochromatin

ABSTRACT: SIRT7 counteracts mesenchymal stem cell senescence via stabilizing heterochromatin

PROVIDER: PRJNA609761 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11216012_1.fastq.gz	Fastqsanger.gz
	SRR11216012_2.fastq.gz	Fastqsanger.gz
	SRR11216013_1.fastq.gz	Fastqsanger.gz
	SRR11216013_2.fastq.gz	Fastqsanger.gz
	SRR11216014_1.fastq.gz	Fastqsanger.gz

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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.

2020-06-29 | GSE146247 | GEO

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Stabilizing heterochromatin by ZKSCAN3 safeguards hMSCs from senescence

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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.

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Stabilization of Heterochromatin by CLOCK Counteracts hMSC Senescence and Articular Degeneration

Project description:Accumulating evidence indicates the close association between the circadian clock and the aging process. However, it is unclear whether and how the circadian clock proteins regulate stem cell aging. Here, we identified a noncanonical transcriptional activator-independent role of CLOCK, a core component of the molecular circadian clock machinery, in counteracting human mesenchymal stem cell (hMSC) senescence. CLOCK expression was decreased during hMSC aging. In addition, CLOCK deficiency accelerated hMSC senescence, whereas CLOCK overexpression attenuated physiological and pathological hMSC senescence. Mechanistic studies revealed that CLOCK formed complexes with nuclear lamina proteins and KAP1, thus maintaining heterochromatin architecture and stabilizing genomic repetitive sequences. Finally, gene therapy with lentiviral vectors encoding CLOCK promoted cartilage regeneration and attenuated age-related osteoarthritis in mice. These findings reveal a novel role of CLOCK independent of its transcriptional activation activity in the stabilization of heterochromatin and alleviation of hMSC senescence, providing a potential therapeutic target for treating aging-associated articular degeneration.

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ZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin.

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