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Comparative analysis of replicative and doxorubicin-induced senescence identifies conserved transcriptomic signatures in aging fibroblasts [RNA-Seq1]

ABSTRACT: We established parallel replicative and doxorubicin-induced senescence models in human BJ fibroblasts, demonstrating progressive morphological changes and SA-β-gal activity increases across passages (P3-P33). Molecular analyses confirmed expected senescence markers: p21/p53 upregulation and LMNB1 downregulation at RNA/protein levels. Transcriptomic profiling identified 734 upregulated (extracellular matrix organization) and 195 downregulated (cell cycle) genes. Comparative lncRNA analysis revealed 23 consistently upregulated candidates, with PURPL showing the most dramatic senescence-associated induction. These validated models provide a robust platform for mechanistic aging studies, with PURPL emerging as a key regulator of cellular senescence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301164 | GEO | 2025/12/02

REPOSITORIES: GEO

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PURPL bidirectionally controls senescence: depletion rejuvenates fibroblasts while overexpression accelerates aging [RNA-Seq2]

Project description:ellular senescence is a fundamental driver of aging and age-related diseases, with long non-coding RNAs (lncRNAs) emerging as critical regulators of this process. Here, we identify PURPL as a bidirectional modulator of senescence in human fibroblasts. Through comparative transcriptomic analysis of replicative and doxorubicin-induced senescence models, we discovered PURPL as the most significantly upregulated lncRNA common to both systems. CRISPR interference (CRISPRi)-mediated PURPL depletion in senescent cells reversed hallmark aging phenotypes, including restoration of LMNB1 expression, suppression of p21, and reduced SA-β-gal activity. Conversely, PURPL overexpression in young fibroblasts recapitulated senescence signatures, inducing extracellular matrix reorganization and cell cycle arrest pathways. RNA-seq revealed PURPL overexpression dysregulated 1,633 genes, mirroring natural aging transcriptomes. These opposing effects establish PURPL as a central regulator of cellular senescence, suggesting its therapeutic potential for age-related conditions. Our findings provide mechanistic insights into lncRNA-mediated senescence control and highlight PURPL as a novel target for aging intervention strategies.

2025-12-02 | GSE301166 | GEO

Targeting PURPL RNA Enabled Rejuvenation of Senescence Cells via Epigenetic Reprogramming

Project description:Cellular senescence is a fundamental driver of ageing and age-related diseases, characterized by irreversible growth arrest and profound epigenetic alterations. While long non-coding RNAs (lncRNAs) have emerged as key regulators of senescence, their potential for senescent cell rejuvenation remains unexplored. Here, we identify the ageing-associated lncRNA PURPL as an epigenetic regulator that controls cellular rejuvenation through H3K9me3-mediated transcriptional silencing. CRISPRi-mediated PURPL depletion produces striking rejuvenation effects, resulting in restored youthful cell morphology, as well as suppression of senescence markers such as p21 and SA-β-gal. Conversely, PURPL overexpression accelerates cellular senescence, recapitulating the transcriptional and phenotypic hallmarks of ageing. Mechanistically, nuclear-localized PURPL regulates H3K9me3 deposition at 411 genomic loci including SERPINE1 (PAI-1) and EGR1, which are key senescence drivers. PURPL-mediated H3K9me3 loss at these loci derepresses their transcription, establishing a pro-senescence gene expression program. These findings reveal that PURPL is an epigenetic modulator of senescence and highlight its potential as a therapeutic target for age-related pathologies.

2025-10-27 | PXD068664 | Pride

PURPL plays a role in epigenetic regulation of gene expression [ChIP-Seq]

Project description:Cellular senescence involves heterochromatin reorganization and aberrant gene expression. We demonstrate that the nuclear-enriched lncRNA PURPL regulates senescence-associated chromatin dynamics by modulating H3K9me3 deposition. PURPL knockdown increased global H3K9me3 levels while its overexpression reduced this repressive mark. Genome-wide analysis revealed 411 loci with PURPL-dependent H3K9me3 changes, including the aging-related gene SERPINE1, where H3K9me3 accumulation correlated with transcriptional repression. These findings establish PURPL as an epigenetic regulator of senescence through targeted control of heterochromatin formation.

2025-12-02 | GSE301169 | GEO

Redistribution of the Lamin B1 genomic binding profile affects spatial rearrangement of heterochromatic domains and gene expression during senescence

Project description:Senescence is a stress responsive form of stable cell cycle exit. Senescent cells have a distinct gene expression profile, which is often accompanied by the spatial redistribution of heterochromatin into senescence-associated heterochromatic foci (SAHFs). Studying a key component of the nuclear lamina, lamin B1 (LMNB1), we report dynamic alterations in its genomic profile and their implications for SAHF formation and gene regulation during senescence. Genome-wide mapping reveals that LMNB1 is depleted during senescence, preferentially from the central regions of lamina-associated domains (LADs), which are enriched for H3K9me3. LMNB1 knockdown facilitates the spatial relocalization of perinuclear H3K9me3, thus promoting SAHF formation, which is inhibited by ectopic LMNB1 expression. Furthermore, despite the global reduction in LMNB1 protein levels, LMNB1 binding increases during senescence in a small subset of gene-rich regions where H3K27me3 also increases and gene expression becomes repressed. These results suggest that LMNB1 may contribute to senescence in at least two ways due to its uneven genomewide redistribution: firstly through the spatial re-organization of chromatin and, secondly, through gene repression. ChIP-seq for Lamin B1 in Growing and Ras Induced Senescence

2013-08-22 | E-GEOD-49341 | biostudies-arrayexpress

The effect of rapamycin upon the enhancer landscape in the context of replicative senescence

Project description:ChIPs of the histone modifications H3K27ac and H3K4me2, which mark enhancers and promoters, were examined during the course of replicative senescence in BJ fibroblasts that were grown in the presence or absence of rapamycin.

2025-05-30 | GSE146566 | GEO

Redistribution of the Lamin B1 genomic binding profile affects spatial rearrangement of heterochromatic domains and gene expression during senescence

2013-08-22 | GSE49341 | GEO

Regulation of Lipids is Central to Replicative Senescence

Project description:Cellular replicative senescence, a state of permanent cell-cycle arrest that occurs following an extended period of cell division in culture, has been linked to organismal aging, tissue repair and tumorigenesis. In this study, we comparatively investigated the global lipid profiles and mRNA content of proliferating and senescent-state BJ fibroblast cells. We found that both the expression levels of lipid-regulating genes, as well as the abundance of specific lipid families, are actively regulated. We further found that 19 polyunsaturated triacylglycerol species showed the most prominent changes during replicative senescence. We argue that diversion of polyunsaturated fatty acids to glycerolipid biosynthesis could be responsible for the accumulation of specific triacylglycerols. This, in turn, could be one of the cellular mechanisms to prevent lipotoxicity under increased oxidative stress conditions observed during replicative senescence. Collectively, our results place regulation of specific lipid species to a central role during replicative senescence.

2017-03-31 | GSE94280 | GEO

Senescence Biomarker Discovery by LC-MS-based Proteomics

Project description:Senescence is a permanent cell cycle arrest that occurs in response to cellular stress. Because senescent cells promote age-related disease, there has been considerable interest in defining the proteomic alterations in senescent cells. Because senescence differs greatly depending on cell type and senescence inducer, continued progress in the characterization of senescent cells is needed. Here, we analyzed primary human mammary epithelial cells (HMECs), a model system for aging, using mass spectrometry-based proteomics. By integrating data from replicative senescence, immortalization by telomerase reactivation, and drug-induced senescence, we identified a robust proteomic signature of HMEC senescence consisting of 77 upregulated and 36 downregulated proteins. This approach identified known biomarkers, such as downregulation of the nuclear lamina protein lamin-B1 (LMNB1), and novel upregulated proteins including the β-galactoside-binding protein galectin-7 (LGALS7). Gene ontology enrichment analysis demonstrated that senescent HMECs upregulated lysosomal proteins and downregulated RNA metabolic processes. We additionally integrated our proteomic signature of senescence with transcriptomic data from senescent HMECs to demonstrate that our proteomic signature can discriminate proliferating and senescent HMECs even at the transcriptional level. Taken together, our results demonstrate the power of proteomics to identify cell type-specific signatures of senescence and advance the understanding of senescence in primary HMECs.

2021-09-28 | PXD027318 | Pride

Replicative senescence is associated with nuclear reorganization and DNA methylation at specific transcription factor binding sites (MBD-seq)

Project description:Primary cells enter replicative senescence after a limited number of cell divisions. This process is associated with reproducible changes in DNA methylation (DNAm) at specific sites in the genome. The mechanism that drives senescence-associated DNAm changes remains unknown and may arise through drift in DNAm or through regulated, senescence dependent modifications at specific sites in the genome. In this study, we analyzed the reorganization of nuclear architecture and DNA methylation during long-term culture of human fibroblasts and mesenchymal stromal cells (MSCs). [MethylCap-seq] Fibroblasts of two female donors (both 43 years old) were culture expanded and DNA was harvested of 10,000,000 cells at early passage (P3 or P5) and late passage (P30 and P33). DNA methylation changes were subsequently analyzed by MethylCap-Seq.

2015-03-26 | E-GEOD-59960 | biostudies-arrayexpress

Transcriptome-profiling (RNA-seq) and Ribosome-profiling (Ribo-seq) in proliferation, quiescence, senescence and transformed states.

Project description:We applied in parallel RNA-Seq and Ribosome-profiling analyses to immortalized human primary BJ fibroblast cells under the following conditions: normal proliferation, quiescence (induced by serum depletion), senescence (induced by activation of the oncogenic RASG12V gene, and examined at early (5 days; pre-senescent state) and late (14 days; fully senescent state) time points), and neoplastic transformation (induced by RASG12V in the background of stable p53 and p16INK4A knockdowns and SV40 small-T expression. RNA-seq, using Illumina HiSeq 2000, was applied to BJ cells under 5 conditions: proliferation, quiescence, pre-senescence, full-senescence, and transfomed. Ribosome profiling, using Illumina HiSeq 2000, was applied to BJ cells under 5 conditions: proliferation, quiescence, pre-senescence, full-senescence, and transfomed.

2013-03-24 | E-GEOD-42509 | biostudies-arrayexpress

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