Increased expression of FOXM1 delays natural and progeroid aging phenotypes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA795140 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17465585.fastq.gz | Fastqsanger.gz | |||
| SRR17465586.fastq.gz | Fastqsanger.gz | |||
| SRR17465587.fastq.gz | Fastqsanger.gz | |||
| SRR17465588.fastq.gz | Fastqsanger.gz | |||
| SRR17465589.fastq.gz | Fastqsanger.gz |
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Project description:The FOXM1 member of the forkhead family of transcription factors is known for its pleiotropic C-terminus transcriptional and N-terminus non-transcriptional functions in a wide set of biological processes critical for cellular homeostasis. We previously found that FOXM1 repression during cellular aging accounts for the accrual of senescence phenotypes, which were vastly restored by overexpressing transcriptionally active FOXM1. Here, we found cyclic induction of a N-terminus truncated FOXM1 transgene on progeroid and naturally aged mice, to offset an aging-associated repression of full-length endogenous FoxM1, thereby allowing reinstatement of both transcriptional and non-transcriptional functions. This translated into mitigation of molecular and histopathological progeroid features of progeroid mice, significantly extending its lifespan. Notably, FOXM1 transgene induction also delayed the progressive accumulation of aging phenotypes, while extending the lifespan of naturally aged mice.
2022-01-10 | GSE193147 | GEO
Project description:DNA methylation in progeroid syndromes
| PRJNA544684 | ENA
Project description:Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. In higher eukaryotes, constitutive heterochromatin is mostly segregated at the nuclear periphery, where the interaction with the nuclear lamina makes the genome more resistant to transcription. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here we show that LINE-1 (L1) RNA accumulation is an early event in both typical and atypical progeroid syndromes. Depletion of L1 RNA in cells from different progeroid syndrome patients using specific antisense oligonucleotides (ASO) restores the levels of heterochromatin epigenetic marks, reverses DNA methylation age and counteracts the expression of senescence-associated genes. Moreover, proteome profiling involved in senescence phenotype was partially restored upon depletion of LINE-1 RNA in both Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner syndrome (WRN-/-).
2022-11-02 | PXD032944 | Pride
Project description:Aims: Cardiac fibroblasts (CFs) play a crucial role in cardiac remodelling, which is a common cause of heart failure (HF). However, the molecular mechanisms underlying the fibroblast-to-myofibroblast transition remain largely unknown. Foxm1 is well known in various cardiopulmonary pathologies. However, Foxm1-driven CF activation in the progression of cardiac remodelling to HF remains to be investigated. Methods: Changes in Foxm1 expression were assessed in samples from patients with HF and mice with transverse aortic constriction (TAC)-induced cardiac remodelling. Pharmacologic antagonist FDI-6 was used to explore the effects of Foxm1 inhibition on post-TAC outcomes. Tcf21-Cre and PostnMCM were used to evaluate Foxm1 loss- and gain-of-function in CFs and myofibroblasts, respectively. Cardiac function and remodelling were examined by echocardiography and histological analysis. Foxm1 downstream target genes were identified by mass spectrometry (MS) and transcriptomic analysis. Post-translational regulation was evaluated by in vitro chromatin immunoprecipitation, co-immunoprecipitation, and ubiquitination assays. Pharmacological inhibition of Usp10 or knockout of p38γ in vivo verified the signalling pathway by which Foxm1 regulated cardiac remodelling. Results: Foxm1 was upregulated in human HF samples as well as in the mouse cardiac remodelling model. CFs were the primary cell type responsible for Foxm1 upregulation. Foxm1 pharmacological inhibition or genetic knockout in CFs or myofibroblasts significantly attenuated TAC-induced cardiac remodelling and HF. Conversely, conditional overexpression of Foxm1 in CFs or myofibroblasts resulted in more severe pathological cardiac remodelling and dysfunction. Combined RNA-sequencing and MS analysis revealed that Foxm1 promoted Usp10 expression by binding to its promoter. Usp10 interacted with p38γ, resulting in p38γ deubiquitination and thus influencing the downstream p38 mitogen-activated protein kinase (MAPK) signalling pathway. Pharmacological inhibition of Usp10 or genetic knockout of p38γ ameliorated the exacerbated TAC-induced cardiac remodelling in mice with myofibroblast-specific Foxm1 overexpression. Conclusion: Our findings reveal an essential role of Foxm1 in CF activation during cardiac remodelling. These results suggest that targeting the Foxm1/Usp10/p38γ MAPK axis may represent a new potential therapeutic strategy against pathological cardiac remodelling and HF.
2024-03-03 | PXD050281 | Pride
Project description:Aims: Cardiac fibroblasts (CFs) play a crucial role in cardiac remodelling, which is a common cause of heart failure (HF). However, the molecular mechanisms underlying the fibroblast-to-myofibroblast transition remain largely unknown. Foxm1 is well known in various cardiopulmonary pathologies. However, Foxm1-driven CF activation in the progression of cardiac remodelling to HF remains to be investigated. Methods: Changes in Foxm1 expression were assessed in samples from patients with HF and mice with transverse aortic constriction (TAC)-induced cardiac remodelling. Pharmacologic antagonist FDI-6 was used to explore the effects of Foxm1 inhibition on post-TAC outcomes. Tcf21-Cre and PostnMCM were used to evaluate Foxm1 loss- and gain-of-function in CFs and myofibroblasts, respectively. Cardiac function and remodelling were examined by echocardiography and histological analysis. Foxm1 downstream target genes were identified by mass spectrometry (MS) and transcriptomic analysis. Post-translational regulation was evaluated by in vitro chromatin immunoprecipitation, co-immunoprecipitation, and ubiquitination assays. Pharmacological inhibition of Usp10 or knockout of p38γ in vivo verified the signalling pathway by which Foxm1 regulated cardiac remodelling. Results: Foxm1 was upregulated in human HF samples as well as in the mouse cardiac remodelling model. CFs were the primary cell type responsible for Foxm1 upregulation. Foxm1 pharmacological inhibition or genetic knockout in CFs or myofibroblasts significantly attenuated TAC-induced cardiac remodelling and HF. Conversely, conditional overexpression of Foxm1 in CFs or myofibroblasts resulted in more severe pathological cardiac remodelling and dysfunction. Combined RNA-sequencing and MS analysis revealed that Foxm1 promoted Usp10 expression by binding to its promoter. Usp10 interacted with p38γ, resulting in p38γ deubiquitination and thus influencing the downstream p38 mitogen-activated protein kinase (MAPK) signalling pathway. Pharmacological inhibition of Usp10 or genetic knockout of p38γ ameliorated the exacerbated TAC-induced cardiac remodelling in mice with myofibroblast-specific Foxm1 overexpression. Conclusion: Our findings reveal an essential role of Foxm1 in CF activation during cardiac remodelling. These results suggest that targeting the Foxm1/Usp10/p38γ MAPK axis may represent a new potential therapeutic strategy against pathological cardiac remodelling and HF.
2024-03-10 | PXD050300 | Pride
Project description:FOXM1 is a key transcription factor regulating cell cycle progression, DNA damage response, and a host of other hallmark cancer features, but the role of the FOXM1 cistrome in driving estrogen receptor-positive (ER+) vs. ER- breast cancer clinical outcomes remains undefined. Chromatin immunoprecipitation sequencing (ChIP-Seq) coupled with RNA sequencing (RNA-Seq) analyses was used to identify FOXM1 target genes in breast cancer cells (MCF-7) where FOXM1 expression was either induced by cell proliferation or repressed by p53 upregulation.
2015-10-26 | E-GEOD-72977 | biostudies-arrayexpress
Project description:FOXM1 is a key transcription factor regulating cell cycle progression, DNA damage response, and a host of other hallmark cancer features, but the role of the FOXM1 cistrome in driving estrogen receptor-positive (ER+) vs. ER- breast cancer clinical outcomes remains undefined. Chromatin immunoprecipitation sequencing (ChIP-Seq) coupled with RNA sequencing (RNA-Seq) analyses was used to identify FOXM1 target genes in breast cancer cells (MCF-7) where FOXM1 expression was either induced by cell proliferation or repressed by p53 upregulation.
2015-10-26 | E-GEOD-73370 | biostudies-arrayexpress
Project description:Fork-head box protein M1 (FoxM1) is a transcription factor which plays critical roles in development and progression of multiple cancers, including human hepatocellular carcinoma (HCC). However, the regulatory mechanism of FoxM1 itself remains largely unclear. Here, we discovered a novel role of abnormal spindle-like microcephaly associated (ASPM) in HCC, which binds to FoxM1 protein and enhances its stability by preventing proteasome-mediated degradation. ChIP-sequencing data showed that ASPM and FoxM1 co-occupies on the promoter region of multiple genes to promote their transcriptions, leading to the enhancement of a FoxM1-driven oncogenic progression. Intriguingly, FoxM1 binds to the promoter region of ASPM and transcriptionally activates the ASPM expression. Furthermore, data from clinical samples showed that a higher co-expression of ASPM and FoxM1 significantly correlates with poor prognosis in HCC, indicating that a positive feedforward loop between ASPM and FoxM1 coordinately promotes the aggressive progression in HCC. Collectively, our study reveals that reciprocal regulation of ASPM and FoxM1 amplifies the oncogenic progression and emphasizes an ASPM-FoxM1 feedforward loop could be a potential biomarker and therapeutic target in HCC.
2024-11-01 | GSE218100 | GEO
Project description:Progeroid syndromes are rare genetic disorders that phenotypically resemble natural aging. Despite identification of causal mutations, mechanisms that generate their clinical manifestations remain elusive. Here, we identified a DNA replication timing (RT) signature that distinguishes progeroid syndromes from normal aging and identifies TP63 gene as a new disease marker. Abnormal TP63 RT appears early during differentiation of progeroid iPSCs and is associated with altered gene variant expression. Our findings demonstrate the utility of RT signatures to identify novel biomarkers not detected by other methods, reveal abnormal TP63 RT as an early event in progeroid disease progression and offer TP63 gene regulation as a potential therapeutic target.
2017-11-16 | GSE98472 | GEO
Project description:Progeroid syndromes are rare genetic disorders that phenotypically resemble natural aging. Despite identification of causal mutations, mechanisms that generate their clinical manifestations remain elusive. Here, we identified a DNA replication timing (RT) signature that distinguishes progeroid syndromes from normal aging and identifies TP63 gene as a new disease marker. Abnormal TP63 RT appears early during differentiation of progeroid iPSCs and is associated with altered gene variant expression. Our findings demonstrate the utility of RT signatures to identify novel biomarkers not detected by other methods, reveal abnormal TP63 RT as an early event in progeroid disease progression and offer TP63 gene regulation as a potential therapeutic target.
2017-11-16 | GSE98471 | GEO