Chromobox homolog 4 overexpression inhibits TNF-α-induced matrix catabolism and senescence by suppressing activation of the NF-κB signaling pathway in nucleus pulposus cells
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE210297 | GEO | 2022/08/05
REPOSITORIES: GEO
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Project description:Abnormal mechanical load is a main risk factor of intervertebral disc degeneration (IDD), and cellular senescence is a pathological change in IDD. Additionally, extracellular matrix (ECM) stiffness promotes human nucleus pulposus cells (hNPCs) senescence. However, the molecular mechanism underlying mechano-induced cellular senescence and IDD progression is not yet fully elucidated. First, we demonstrated that mechano-stress promoted hNPCs senescence via NF-κB signaling. Subsequently, we identified periostin as the main mechano-responsive molecule in hNPCs through unbiased sequencing, which was transcriptionally upregulated by NF-κB p65; moreover, secreted periostin by senescent hNPCs further promoted senescence and upregulated the catabolic process in hNPCs through activating NF-κB, forming a positive loop. Both Postn (encoding periostin) knockdown via siRNA and periostin inactivation via neutralizing antibodies alleviated IDD and NPCs senescence. Furthermore, we found that mechano-stress initiated the positive feedback of NF-κB and periostin via PIEZO1. PIEZO1 activation by Yoda1 induced severe IDD in rat tails without compression, and Postn knockdown alleviated the Yoda1-induced IDD in vivo. Here, we reported for the first time that self-amplifying loop of NF-κB and periostin initiated via PIEZO1 under mechano-stress accelerated NPCs senescence, leading to IDD. Furthermore, periostin neutralizing antibodies, which may serve as potential therapeutic agents for IDD, interrupted this loop.
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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.
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Project description:Intervertebral disc degeneration (IDD) is an important cause of low back pain. And abnormal mechanical factors are an important contributor to IDD. To identify mechanical responsive miRNAs in IDD, we used a custom-made compression device to establish IDD in rats and considered as IDD group, and the Sham group was inserted with K-wires into coccyxes only. After four weeks, rat nucleus pulposus tissues were obtained for miR-seq analysis.
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Project description:Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. Understanding the dysregulated epigenetics governing LUAD progression is pivotal for identifying therapeutic targets. CBX4, a chromobox protein, is reported to be upregulated in LUAD. However, its regulatory role in LUAD progression warrants in-depth investigation. This study highlights the dual impact of CBX4 on LUAD proliferation and metastasis. Through a series of rigorous in vitro and in vivo experiments, we elucidate that CBX4 functions in promoting LUAD proliferation via upregulating PHGDH expression while concurrently suppressing LUAD metastasis by inhibiting ZEB2 transcription. Further investigation into the underlying mechanism reveals CBX4’s intricate interactions with distinct epigenetic factors. The inhibition of ZEB2 transcription involves CBX4-mediated recruitment of canonical PRC1 (cPRC1), establishing H2K119ub on the ZEB2 promoter. Simultaneously, CBX4 facilitates PHGDH transcription through interaction with GCN5, inducing heightened histone acetylation on the PHGDH promoter. These findings underscore CBX4's pivotal role as a regulator of LUAD progression, emphasizing its diverse transcriptional regulatory functions contingent upon interactions with specific epigenetic partners. Understanding the nuanced interplay between CBX4 and epigenetic factors sheds light on potential therapeutic avenues in LUAD.
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Project description:Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. Understanding the dysregulated epigenetics governing LUAD progression is pivotal for identifying therapeutic targets. CBX4, a chromobox protein, is reported to be upregulated in LUAD. However, its regulatory role in LUAD progression warrants in-depth investigation. This study highlights the dual impact of CBX4 on LUAD proliferation and metastasis. Through a series of rigorous in vitro and in vivo experiments, we elucidate that CBX4 functions in promoting LUAD proliferation via upregulating PHGDH expression while concurrently suppressing LUAD metastasis by inhibiting ZEB2 transcription. Further investigation into the underlying mechanism reveals CBX4’s intricate interactions with distinct epigenetic factors. The inhibition of ZEB2 transcription involves CBX4-mediated recruitment of canonical PRC1 (cPRC1), establishing H2K119ub on the ZEB2 promoter. Simultaneously, CBX4 facilitates PHGDH transcription through interaction with GCN5, inducing heightened histone acetylation on the PHGDH promoter. These findings underscore CBX4's pivotal role as a regulator of LUAD progression, emphasizing its diverse transcriptional regulatory functions contingent upon interactions with specific epigenetic partners. Understanding the nuanced interplay between CBX4 and epigenetic factors sheds light on potential therapeutic avenues in LUAD.
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Project description:Cytotoxic T lymphocyte (CTL) differentiation is controlled by the crosstalk of various transcription factors and epigenetic modulators. Fully uncovering this process is fundamental to improving immunotherapy and designing novel therapeutic approaches. Here, we show that Polycomb Repressive Complex (PRC)1 subunit Chromobox (Cbx)4 favors effector CTL differentiation in murine model. Cbx4 deficiency in CTLs induced transcriptional signature and phenotype of memory cells, increasing the memory CTL population during acute viral infection. It has been previously shown that besides binding to H3K27me3 through its chromodomain, Cbx4 function as a SUMO E3 ligase in a SUMO interacting motifs (SIM)-dependent way. Overexpression of Cbx4 mutants in distinct domains showed that this protein regulates CTL differentiation primarily in a SIM-dependent way and partially through its chromodomain. Our data revealed a novel role of a Polycomb group protein Cbx4 controlling CTL differentiation and indicates the SUMOylation as a key molecular mechanism connected to chromatin modification in this process.
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Project description:Intervertebral disc degeneration (IDD) leads to low back pain and disability globally. Progressive loss of nucleus pulposus cells (NPCs) are associated with the onset of IDD. Cell-based therapy has been shown the promising for many diseases, including the IDD in preclinical studies. However, the limited availability of human NPCs has hurdled such application for IDD. This study aimed to define strategies to derive NPCs from human ESC/iPSC. Human ESC3, ESC9 and IMR-90-iPSC were used for a three-step protocol to direct differentiation toward mesodermal, subsequently notochordal and finally NPCs. Our results showed that notochordal-like cells (NCCs) were successfully derived from the first two-step of protocol confirmed by immunofluorescence staining of Noto, Brachyury (T) and Foxa2. RT-PCR results showed that the expression of Noto, T and Foxa2 was the highest at day 5 after differentiation. Furthermore, these NCCs can be differentiated into NPCs via the final step of the protocol. These NPCs expressed the tyrosine kinase receptor Tie2 (Tie2), disialoganglioside 2 (GD2), collagen II and aggrecan. Genome-wide transcriptomic analyses by sequencing (RNA-seq) further reveals the expression of a wide array of extra-cellular matrix (ECM) genes, up-stream regulators and pathways. Cross-comparison of our RNA-seq profiles with public NPC data confirms the differentiated products are much closer to NPCs than are ESC/iPSC. Co-culturing NPCs with Light2 cell line, a luciferase-based reporter responsive to sonic hedgehog (Shh) secreted protein, showed NPCs synthesized Shh. Transplantation of NPCs effectively attenuated the spinal injury in a puncture-induced disc degeneration (PDD) model in rat. Furthermore, we utilized CRISPR/Cas9 technology to seamlessly knock in an enhanced fluorescent protein (GFP) to the loci of the noto gene in ESC9. Our study demonstrates that NPCs could be induced from human ESC/iPSC. This study provides a cell source for the development of novel strategy for IDD diseases.
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