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Histone Demethylases KDM3A and KDM4C regulate mesenchymal stromal cell senescence and bone aging through condensin-mediated heterochromatin organization

ABSTRACT: Epigenomic changes and stem cell exhaustion are two hallmarks of aging. Accumulating evidence suggest that MSC senescence could perpetuate aging or age-related diseases. Here we report that two H3K9 demethylases KDM3A and KDM4C regulate heterochromatin reorganization via transcriptionally activating condensin components NCAPD2 and NCAPG2 in aging MSCs. Suppression of KDM3A or KDM4C leads to robust DNA damage response and aggravates cellular senescence, whereas overexpression of KDM3A/KDM4C or NCAPD2 directly promotes heterochromatin reorganization and blunts DNA damage response. MSCs derived from kdm3a-/- mice exhibit compromised heterochromatin organization machinery and are more susceptible to genotoxic damage, which are associated with accelerated bone aging. Consistently, analysis of human bone marrow MSCs and transcriptome database for other human adult stem cells reveals inverse correlation of KDM3A and KDM4C with aging. Taken together, the present finding unveils a novel function of histone demethylases as a surveillance mechanism to restrain DNA damage accumulation via transcriptionally activating condensins during stem cell aging, which provides potential targets for the diagnosis and intervention of human aging and geriatric diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133098 | GEO | 2019/12/01

REPOSITORIES: GEO

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Histone Demethylases KDM3A and KDM4C regulate mesenchymal stromal cell senescence and bone aging through condensin-mediated heterochromatin organization

Project description:Histone Demethylases KDM3A and KDM4C regulate mesenchymal stromal cell senescence and bone aging through condensin-mediated heterochromatin organization

| PRJNA549942 | ENA

The loss of heterochromatin is associated with multiscale three-dimensional genome reorganization and aberrant transcription during cellular senescence

Project description:Heterochromatin remodeling is critical for various cell processes. In particular, the “loss of heterochromatin” phenotype in cellular senescence engages with the progress of aging and age-related disorders. Although biological processes of senescent cells including senescence-associated heterochromatin foci (SAHF) formation, chromosome compaction and entry into senescence have been closely associated with high-order chromatin structure. the relationship between the high-order chromatin organization and the loss of heterochromatin phenotype during senescence has not been fully understood. By using senescent and late senescent fibroblasts induced by DNA damage harboring the “loss of heterochromatin” phenotype, we observed progressive 3D reorganization of heterochromatin during senescence. Facultative and constitutive heterochromatin marked by H3K27me3 and H3K9me3, respectively, showed different alterations. Facultative heterochromatin tends to switch from the repressive B-compartment to the active A-compartment, whereas constitutive heterochromatin shows no significant changes at the compartment level but enhanced interactions between themselves. Interestingly, both types show increased chromatin accessibility and gene expression leakage during senescence. Furthermore, increased chromatin accessibility in potential CTCF binding sites accompanies by the establishment of novel loops in constitutive heterochromatin. Finally, we also observed aberrant expression of repetitive elements, including LTR (long terminal repeat) and satellite classes. Overall, facultative and constitutive heterochromatin show multiscale but distinct alterations in the 3D map, meanwhile they also share the same features of increased chromatin accessibility and gene expression leakage. This study provides an epigenomic map of heterochromatin reorganization during senescence.

2019-12-31 | GSE133292 | GEO

Dynamics of de novo heterochromatin assembly and disassembly at replication forks ensures fork stability

Project description:Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here, we discover a checkpoint regulated cascade of chromatin signaling that activates 5 the histone methyltransferase EHMT2/G9a to catalyze heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fiber approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favored by the G9a-dependent exclusion of the H3K9-demethylase 10 JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering ssDNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help explaining chemotherapy resistance and poor prognosis observed in cancer patients displaying elevated level of G9a/H3K9me3.

2023-05-12 | PXD041742 | Pride

Nuclear SIRT3 counteracts human stem cell senescence

Project description:Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase involved in various physiological and pathological processes. However, the role of SIRT3 in regulating human stem cell senescence remains largely unknown. Here, we observed the downregulated expression of SIRT3 in senescent human mesenchymal stem cells (hMSCs). SIRT3 deficiency accelerated cellular senescence in hMSCs, along with compromised nuclear integrity, loss of heterochromatin and increased DNA damage. These aging-associated nuclear defects were attenuated by the reintroduction of SIRT3. Mechanistic studies demonstrated the interaction of SIRT3 with nuclear envelope proteins and heterochromatin-associated proteins. Further findings revealed that SIRT3 deficiency led to the loss of lamina-associated domains (LADs) from the nuclear lamina, increased chromatin accessibility and aberrant transcription of repetitive sequences. Meanwhile, the overexpression of nuclear-localized SIRT3 rescued the senescence phenotypes. Taken together, our study reveals a novel role of nuclear SIRT3 in stabilizing heterochromatin and counteracting hMSC senescence, which may provide new clinical therapeutic targets to ameliorate aging-related diseases.

2021-09-09 | PXD023479 | Pride

H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence (expression)

Project description:Cellular senescence is a tumor-suppressive program that involves chromatin reorganization and specific changes in gene expression that trigger an irreversible cell-cycle arrest. We have examined the effect of suppressing the histone demethylases Jarid1a and Jarid1b on the senescence-associated gene expression signatures. Human fibroblast (IMR90) cells were infected with retroviral vectors expresssing shRNA targeting Jarid1a, Jarid1b or both, and triggered to undergo quiescence by removal of serum or senescence by over-expression of activated ras (Hrasv12).

2013-01-31 | E-GEOD-43920 | biostudies-arrayexpress

H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence (expression)

2013-01-31 | GSE43920 | GEO

Proteomic analysis of small extracellular vesicles derived from human ESCs

Project description:Tissue-resident stem cell senescence leads to stem cell exhaustion, which is a major cause of physiological and pathological aging. Stem cells-derived extracellular vesicles(SCs-EVs) have been reported to possess therapeutic potential in preclinical studies for diverse diseases. However, whether SCs-EVs could rejuvenate senescent tissue stem cell to prevent age-related disorders still remains unknown. Here, we showed that chronic application of human embryonic stem cells-derived extracellular vesicles (hESCs-sEVs) rescues senescent bone marrow MSCs (BM-MSCs) function and prevents age-related bone loss in aging mice. Transcriptome analysis revealed that hESCs-sEVs treatment up-regulates the expression of genes involved in anti-aging, stem cell proliferation and osteogenic differentiation in BM-MSCs. Furthermore, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis identified 4122 proteins encapsulated in hESCs-sEVs. Bioinformatics analysis predicated that protein components in the hESCs-sEVs function in a synergistic way to induce the activation of several canonical signaling pathways, including Wnt, Sirtuin, AMPK, PTEN signaling, which results in the up-regulation of anti-aging genes in BM-MSCs and then the recovery of senescent BM-MSCs function. Collectively, our findings reveal the effect of hESCs-sEVs in reversing BM-MSCs senescence and age-related osteogenic dysfunction, and thereby preventing age-related bone loss. Given that hESCs-sEVs could alleviate senescence of tissue-resident stem cells, it might be a promising therapeutic candidate for age-related diseases.

2021-08-30 | PXD018655 | Pride

CRISPR screening identifies nucleolar RPL22 as a heterochromatin destabilizer and senescence driver

Project description:Dysfunction of the ribosome manifests during cellular senescence and contributes to tissue aging, functional decline, and development of aging-related disorders in ways that have remained enigmatic. Here, we conducted a comprehensive CRISPR-based loss-of-function (LOF) screen of ribosome-associated genes (RAGs) in human mesenchymal progenitor cells (hMPCs). Through this approach, we identified ribosomal protein L22 (RPL22) as the foremost RAG whose deficiency mitigates the effects of cellular senescence. Consequently, absence of RPL22 delays hMPCs from becoming senescent, while an excess of RPL22 accelerates the senescence process. Mechanistically, we found in senescent hMPCs, that RPL22 accumulates within the nucleolus. This accumulation triggers a cascade of events, including heterochromatin decompaction with concomitant degradation of key heterochromatin proteins, specifically heterochromatin protein 1γ (HP1γ) and heterochromatin protein KRAB-associated protein 1 (KAP1). Subsequently, RPL22-dependent breakdown of heterochromatin stimulates the transcription of ribosomal RNAs (rRNAs), triggering cellular senescence. In summary, our findings unveil a novel role for nucleolar RPL22 as a destabilizer of heterochromatin and a driver of cellular senescence, shedding new light on the intricate mechanisms underlying the aging process.

2024-02-14 | GSE253231 | GEO

KDM4C epigenetically regulates and forms a feed-forward loop with ALDH1A3 to maintain gastric cancer stemness

Project description:Gastric cancer (GC) stem cells (GCSCs) are characterized as high level of ALDH activity, however, the mechanisms of maintenance of high ALDH activity and stemness in GCSCs are largely unknown. Here, we report that KDM4C, a H3K9me2/3-demethylase, epigenetically regulates ALDH1A3 by histone demethylation and forms a feed-forward loop with ALDH1A3 to supports GS stemness. Ectopic expression of both KDM4C and ALDH1A3 promotes the properties of GCSCs, including spherogenecity, self-renewal, CD44 expression and ALDH activity; knockdown of anyone abolished the effect of each other. KDM4C directly binds to the promoter of ALDH1A3, leads to histone demethylation, thereby promoting ALDH1A3 transcription. Upregulated ALDH1A3 in turn transcriptionally upregulates KDM4C. Simultaneous inhibition of KDM4C and ALDH1A3 synergistically sensitizes GC sphere-derived cells to traditional chemotherapeutic drugs. The finding that upregulated ALDH1A3 promotes its own transcription via KDM4C-mediated epigenetic modification represents an important feed-forward mechanism for GCSCs to maintain stemness and promote tumourigenesis and our work thus suggests a novel therapeutic strategy for eradicating human GCSCs. To investigate the mechanisms underlying KDM4C promoting CG stemness, we identified the differentially expressed proteins (DEPs) between KDM4C-overexpressing and control AGS cells by iTRAQ-based quantitative proteomic analysis.

2022-02-16 | PXD023455 | Pride

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

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