Hepatocyte‑specific Ccnd1 knockout in aged mice reduces inflammatory signaling
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ABSTRACT:
PROVIDER: PRJNA1299809 | ENA |
REPOSITORIES: ENA
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Project description:We performed hepatocyte‑specific knockout of Ccnd1 in 17‑month‑old C57BL/6J mice using AAV8‑TBG‑saCas9 with Ccnd1‑targeting sgRNA versus Rosa26 control. After 3 weeks, livers were harvested for bulk RNA‑seq to assess effects of elevated Ccnd1 with age.
2025-08-13 | GSE304265 | GEO
Project description:Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6–dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.
2025-08-13 | GSE304160 | GEO
Project description:Liver cancer incidences increase beyond 55 years of age suggesting that molecular and immunological changes accompanying aging contribute critically to tumor initiation. However, the mechanisms linking aging and liver cancer initiation are not well understood. Our study investigates the role of CD44, a transmembrane glycoprotein implicated in cancer development, in aging-associated liver pathophysiology. CD44 expression was analyzed in young and aged mouse livers, with aged livers showing an accumulation of CD44 expressing hepatocytes. Analyses by single nucleus RNA sequencing reveal that CD44 expressing hepatocytes in aged livers exhibit enrichment of immune modulatory genes and interferon associated pathways. Spatial analyses showed that CD44 expression in hepatocytes co-occurs with T-cell neighborhoods exhibiting reduced cytokine expression. Functional assays showed reduced antigen-specific IFN-γ production by adoptively transferred, ex vivo activated young CD8+ T cells in the aged liver environment. Finally, aged livers lacking hepatocyte CD44 showed attenuation in immune-associated and fibrosis-related gene signatures, consistent with a role for hepatocyte CD44 in age-associated inflammation and early fibrosis. Our findings identify an aging-associated hepatocyte CD44 state that co-occurs with immune modulation and early fibrotic cues, overall suggestive of an early cancer-initiating niche signature in aged livers.
2026-02-18 | GSE309965 | GEO
Project description:GRSF1 deficiency in skeletal muscle reduces endurance in aged mice
| PRJNA722912 | ENA
Project description:Liver cancer incidences increase beyond 55 years of age suggesting that molecular, cellular and tissue changes accompanying aging contribute critically to tumor initiation. However, the mechanisms linking aging and liver cancer initiation are not well understood. Our study investigates the role of CD44, a transmembrane glycoprotein and a known marker of tumor-initiating cells (TICs), in age-associated liver pathophysiology. Aged livers showed an accumulation of CD44 expressing hepatocytes. Single nucleus RNA sequencing revealed that CD44 expressing hepatocytes in aged livers exhibit enrichment of immune modulatory genes and activation of the IL6/JAK/Stat3 pathway. Spatial analyses confirmed upregulation of the IL6/JAK/Stat3 pathway and showed that CD44-expressing hepatocytes are proximal to T-cell neighborhoods exhibiting reduced cytokine expression. In adoptive transfer assays, ex vivo-activated CD8+ T cells mounted a lower antigen-specific IFNg response in aged livers than in young liver, consistent with an immune suppressive aged milieu. Hepatocyte-specific loss of Cd44 expression in aged livers compromised IL6/JAK/Stat3 activity and other immune/fibrotic gene signatures, supporting a contribution of hepatocyte Cd44 to age-associated immune dysregulation and early fibrosis. Our findings identify an aging-associated hepatocyte CD44 state with IL6/JAK/Stat3 activation, blunted T cell effector signals and early fibrotic cues.
2026-02-18 | GSE310240 | GEO
Project description:Aims: CCND1 amplification was an unfavorable prognostic factor for patients with melanoma. This study aimed to investigate the molecular changes in tumor of B16 with CCND1 overexpression. Methods: High-throughput sequencing was used to identify genes that were differentially expressed in tumor between B16 controls and B16 with CCND1 overexpression. Tumors of B16 Ctrl (n=3) and B16 with CCND1 overexpression (n=3) were enrolled in this study. Results: mRNA expression of genes associated with immunity, such as CD8, Gzm, B2m, and Tap1 were decreased in tumors with CCND1 overexpression. Conclusion: CCND1 overexpression is associated with an immunosuppressive microenvironment.
2022-07-20 | GSE180327 | GEO
Project description:Organ size is maintained by the controlled proliferation of distinct cell populations. In the mouse liver, hepatocytes in the midlobular zone that are positive for cyclin D1 (CCND1) repopulate the parenchyma at a constant rate to preserve liver mass. Here, we investigated how hepatocyte proliferation is supported by hepatic stellate cells (HSCs), pericytes that are in close proximity to hepatocytes. We used T cells to ablate nearly all HSCs in the murine liver, enabling the unbiased characterization of HSC functions. In the normal liver, complete loss of HSCs persisted for up to 10 weeks and caused a gradual reduction in liver mass and in the number of CCND1+ hepatocytes. We identified neurotrophin-3 (Ntf-3) as an HSC-produced factor that induced the proliferation of midlobular hepatocytes through the activation of tropomyosin receptor kinase B (TrkB). Treating HSC-depleted mice with Ntf-3 restored CCND1+ hepatocytes in the midlobular region and increased liver mass. These findings establish that HSCs form the mitogenic niche for midlobular hepatocytes and identify Ntf-3 as a hepatocyte growth factor.
2023-06-27 | GSE211370 | GEO
Project description:A subset of CCND1-negative mantle cell lymphoma MCL (CCND1- MCL) has been recognized, and around half of them harbor CCND2 translocations. To identify other potential mechanisms driving MCL pathogenesis we investigated CCND1− MCL by by whole genome/exome sequencing. We identified a cryptic insertion of IGK and IGL enhancer regions near the CCND3 gene in three cases. Specific FISH probes detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases). In conclusion, virtually all CCND1-/SOX11+ MCL carry CCND2/CCND3 rearrangement with IG genes, including cryptic IGK/L enhancer regions not detected with currently used FISH probes.
| EGAS00001003060 | EGA
Project description:Skeletal muscle contains long multinucleated and contractile structures known as muscle fibers, which arise from the fusion of myoblasts into nucleated myotubes during myogenesis. The myogenic regulatory factor (MRF) MYF5 is the earliest to be expressed during myogenesis and functions as a transcription factor in muscle progenitor cells (satellite cells) and myocytes. In mouse C2C12 myocytes, MYF5 is implicated in the initial steps of myoblast differentiation into myotubes. Ribonucleoprotein immunoprecipitation (RIP) analysis showed that MYF5 bound a subset of myoblast mRNAs; prominent among them was Ccnd1 mRNA, which encodes the key cell cycle regulator CCND1 (Cyclin D1). Biotin-RNA pulldown, UV-crosslinking, and gel shift experiments indicated that MYF5 was capable of binding the 3' untranslated region (UTR) and the coding region (CR) of Ccnd1 mRNA. MYF5 silencing in proliferating growing myoblasts revealed that and MYF5 promoted CCND1 translation, and it also modestly increased transcription of Ccnd1 mRNA. Importantly, silencing MYF5 reduced myoblast growth as well as differentiation of myoblasts into myotubes, while overexpressing MYF5 in C2C12 cells upregulated CCND1 expression. We propose that MYF5 enhances early myogenesis in part by coordinately elevating Ccnd1 transcription and Ccnd1 mRNA translation. Four replicates were utilized from either Control (IgG) or MYF5-immunoprecipitated RNA samples from C2C12 cells growing in either growth medium (GM) or differentiation medium (DM) for a total of sixteen samples.
2016-08-08 | E-GEOD-73704 | biostudies-arrayexpress
Project description:Hepatocyte CD44 in aged mouse liver correlates with immune modulation and fibrotic priming
| PRJNA1364059 | ENA