Super-enhancer-driven core transcription factor FOXP1 delays endothelial cell senescence via phase separation-mediated SESN3 activation_cuttag seq
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE303850 | GEO | 2025/12/10
REPOSITORIES: GEO
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Project description:Rationale: Endothelial cell senescence leads to endothelial dysfunction, thereby promoting the progression of atherosclerosis. Super-enhancers are crucial epigenetic cis-regulatory elements whose extensive reprogramming drives aberrant transcription in human diseases. However, the underlying mechanisms of super-enhancer on endothelial cell senescence remain unclear.
2025-12-10 | GSE303848 | GEO
Project description:Phase separation, a biophysical process that segregates subcellular environments into condensates, is recognized for its role in regulating transcription. However, the extent of its influence on cellular senescence processes remains to be fully elucidated. Here, we have established that the depletion of MRG15, a conserved chromodomainprotein, leads to cellular senescence in human mesenchymal stem cells (hMSCs). MRG15 is capable of forming phase-separated liquid condensates via its intrinsically disordered region (IDR). Through the utilization of IDR deletion and replacement assays, we have shed light on the pivotal role that MRG15 condensation plays in the senescence of hMSCs. Through epigenomic and transcriptomic analysis, the depletion of MRG15 impacts pathways that are integral to the cell cycle and the senescence process, as evidenced by the diminished binding and the modified expression of key genes, including CDKN1A, LMNB1, CCNB1, NPM1, MYC, and HMGB2. Within a bleomycin-induced model of idiopathic pulmonary fibrosis in mice, hMSCs of the wild-type variety were able to ameliorate inflammation and fibrosis, a stark contrast to the outcomes observed in MSCs where MRG15 was knocked down or its IDR was deleted. Our findings establishes a link between phase separation and senescence regulation and could present a promising new therapeutic target for the alleviation of age-related diseases and the potential extension of lifespan.
2025-04-02 | GSE274376 | GEO
Project description:Phase separation, a biophysical process that segregates subcellular environments into condensates, is recognized for its role in regulating transcription. However, the extent of its influence on cellular senescence processes remains to be fully elucidated. Here, we have established that the depletion of MRG15, a conserved chromodomainprotein, leads to cellular senescence in human mesenchymal stem cells (hMSCs). MRG15 is capable of forming phase-separated liquid condensates via its intrinsically disordered region (IDR). Through the utilization of IDR deletion and replacement assays, we have shed light on the pivotal role that MRG15 condensation plays in the senescence of hMSCs. Through epigenomic and transcriptomic analysis, the depletion of MRG15 impacts pathways that are integral to the cell cycle and the senescence process, as evidenced by the diminished binding and the modified expression of key genes, including CDKN1A, LMNB1, CCNB1, NPM1, MYC, and HMGB2. Within a bleomycin-induced model of idiopathic pulmonary fibrosis in mice, hMSCs of the wild-type variety were able to ameliorate inflammation and fibrosis, a stark contrast to the outcomes observed in MSCs where MRG15 was knocked down or its IDR was deleted. Our findings establishes a link between phase separation and senescence regulation and could present a promising new therapeutic target for the alleviation of age-related diseases and the potential extension of lifespan.
2025-04-02 | GSE274296 | GEO
Project description:Phase Separation of MRG15 delays cellular senescence
| PRJNA1146139 | ENA
Project description:Endothelial cell senescence is one of the most important causes of vascular dysfunction and atherosclerosis. Circular RNAs (circRNAs) are endogenous RNA molecules with covalently closed-loop structures, which have been reported to be abnormally expressed in many human diseases. However, the potential role of circRNAs in endothelial cell senescence remains unknown. Here, we compared the expression patterns of circRNAs in young and senescent human endothelial cells using RNA sequencing. Among the differentially expressed endothelial cell senescence-associated circRNAs, we identified circGNAQ, generated by circularization of exons 4 and 5 of the GNAQ gene, as a circRNA showing markedly reduced levels in senescent endothelial cells. CircGNAQ silencing in young endothelial cells triggered senescence, as determined by a rise in senescence-associated β-galactosidase activity, reduced cell proliferation, and suppressed angiogenesis; circGNAQ overexpression showed the opposite effects. Mechanistic studies revealed that circGNAQ acted as an endogenous miR-146a-5p sponge to sequester and inhibit miR-146a-5p activity, leading to increased PLK2 expression. In vivo studies showed that circGNAQ overexpression delayed endothelial cell senescence and atherosclerosis progression in ApoE-/- mice. These results revealed an important role for circGNAQ in cellular senescence and provide novel insight into the role of circRNAs in atherosclerosis progression.
2020-06-18 | GSE151475 | GEO
Project description:Proinflammatory stimuli rapidly and globally remodel chromatin landscape, thereby enabling transcriptional responses. Yet, the mechanisms coupling chromatin regulators to the master regulatory inflammatory transcription factor NF-kB remain poorly understood. We report in human endothelial cells (ECs) that activated NF-kB binds to enhancers, provoking a rapid, global redistribution of BRD4 preferentially at super-enhancers, large enhancer domains highly bound by chromatin regulators. Newly established NF-kB super-enhancers drive nearby canonical inflammatory response genes. In both ECs and macrophages BET bromodomain inhibition prevents super-enhancer formation downstream of NF-kB activation, abrogating proinflammatory transcription. In TNFa-activated endothelium this culminates in functional suppression of leukocyte rolling, adhesion and transmigration. Sustained BET bromodomain inhibitor treatment of LDLr -/- animals suppresses atherogenesis, a disease process rooted in pathological vascular inflammation involving endothelium and macrophages. These data establish BET-bromodomains as key effectors of inflammatory response through their role in the dynamic, global reorganization of super-enhancers during NF-kB activation. Gene expression analysis of human endothelial cells in resting state, treatment with TNFalpha or TNFalpha with the BET bromodomain inhibitor JQ1
2014-09-29 | E-GEOD-53999 | biostudies-arrayexpress
Project description:Proinflammatory stimuli rapidly and globally remodel chromatin landscape, thereby enabling transcriptional responses. Yet, the mechanisms coupling chromatin regulators to the master regulatory inflammatory transcription factor NF-kB remain poorly understood. We report in human endothelial cells (ECs) that activated NF-kB binds to enhancers, provoking a rapid, global redistribution of BRD4 preferentially at super-enhancers, large enhancer domains highly bound by chromatin regulators. Newly established NF-kB super-enhancers drive nearby canonical inflammatory response genes. In both ECs and macrophages BET bromodomain inhibition prevents super-enhancer formation downstream of NF-kB activation, abrogating proinflammatory transcription. In TNFa-activated endothelium this culminates in functional suppression of leukocyte rolling, adhesion and transmigration. Sustained BET bromodomain inhibitor treatment of LDLr -/- animals suppresses atherogenesis, a disease process rooted in pathological vascular inflammation involving endothelium and macrophages. These data establish BET-bromodomains as key effectors of inflammatory response through their role in the dynamic, global reorganization of super-enhancers during NF-kB activation. ChIP-Seq for various transcription factors, RNA Polymerase II, and histone modifications in human endothelial cells
2014-09-29 | E-GEOD-53998 | biostudies-arrayexpress
Project description:Proinflammatory stimuli rapidly and globally remodel chromatin landscape, thereby enabling transcriptional responses. Yet, the mechanisms coupling chromatin regulators to the master regulatory inflammatory transcription factor NF-kB remain poorly understood. We report in human endothelial cells (ECs) that activated NF-kB binds to enhancers, provoking a rapid, global redistribution of BRD4 preferentially at super-enhancers, large enhancer domains highly bound by chromatin regulators. Newly established NF-kB super-enhancers drive nearby canonical inflammatory response genes. In both ECs and macrophages BET bromodomain inhibition prevents super-enhancer formation downstream of NF-kB activation, abrogating proinflammatory transcription. In TNFa-activated endothelium this culminates in functional suppression of leukocyte rolling, adhesion and transmigration. Sustained BET bromodomain inhibitor treatment of LDLr -/- animals suppresses atherogenesis, a disease process rooted in pathological vascular inflammation involving endothelium and macrophages. These data establish BET-bromodomains as key effectors of inflammatory response through their role in the dynamic, global reorganization of super-enhancers during NF-kB activation. Chem-Seq for the biotinylated small molecule JQ1 in untreated or TNFalpha treated human endothelial cells
2014-09-29 | E-GEOD-60051 | biostudies-arrayexpress
Project description:Phase Separation of MRG15 delays cellular senescence [CUT&Tag]
| PRJNA1146141 | ENA
Project description:Phase Separation of MRG15 delays cellular senescence [RNA-Seq]
| PRJNA1145897 | ENA