Form follows function: Nuclear morphology as a quantifiable predictor of cellular senescence
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ABSTRACT:
PROVIDER: PRJNA1245406 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32956178_1.fastq.gz | Fastqsanger.gz | |||
| SRR32956178_2.fastq.gz | Fastqsanger.gz | |||
| SRR32956179_1.fastq.gz | Fastqsanger.gz | |||
| SRR32956179_2.fastq.gz | Fastqsanger.gz | |||
| SRR32956180_1.fastq.gz | Fastqsanger.gz |
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Project description:Enlarged or irregularly shaped nuclei are frequently observed in tissue cells undergoing senescence. However, it remained unclear whether this peculiar morphology is a cause or a consequence of senescence and how informative it is in distinguishing between proliferative and senescent cells. Recent research reveals that nuclear morphology can act as a predictive biomarker of senescence, suggesting an active role for the nucleus in driving senescence phenotypes. By employing deep learning algorithms to analyze nuclear morphology, accurate classification of cells as proliferative or senescent is achievable across various cell types and species both in vitro and in vivo. This quantitative imaging-based approach can be employed to establish links between senescence burden and clinical data, aiding in the understanding of age-related diseases, as well as assisting in disease prognosis and treatment response.
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Project description:Enlarged or irregularly shaped nuclei are frequently observed in tissue cells undergoing senescence. However, it remained unclear whether this peculiar morphology is a cause or a consequence of senescence and how informative it is in distinguishing between proliferative and senescent cells. Recent research reveals that nuclear morphology can act as a predictive biomarker of senescence, suggesting an active role for the nucleus in driving senescence phenotypes. By employing deep learning algorithms to analyze nuclear morphology, accurate classification of cells as proliferative or senescent is achievable across various cell types and species both in vitro and in vivo. This quantitative imaging-based approach can be employed to establish links between senescence burden and clinical data, aiding in the understanding of age-related diseases, as well as assisting in disease prognosis and treatment response.
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Project description:Cortical function is disrupted in neuroinflammatory disorders, including HIV-associated neurocognitive disorders (HAND). Astrocyte dysfunction includes retraction of foot processes from the blood-brain barrier and decreased removal of neurotransmitters from synaptic clefts. Mechanisms of astrocyte activation, including innate immune function and the fine neuroanatomy of astrocytes, however, remain to be investigated. We quantified the number of glial fibrillary acidic protein (GFAP)-labeled astrocytes per square millimeter and the proportion of astrocytes immunopositive for Toll-like receptor 2 (TLR2) to examine innate immune activation in astrocytes. We also performed detailed morphometric analyses of gray and white matter astrocytes in the frontal and parietal lobes of rhesus macaques infected with simian immunodeficiency virus (SIV), both with and without encephalitis, an established model of AIDS neuropathogenesis. Protoplasmic astrocytes (gray matter) and fibrous astrocytes (deep white matter) were imaged, and morphometric features were analyzed using Neurolucida. Gray matter and white matter astrocytes showed no change in cell body size in animals infected with SIV regardless of encephalitic status. In SIV-infected macaques, both gray and white matter astrocytes had shorter, less ramified processes, resulting in decreased cell arbor compared with controls. SIV-infected macaques with encephalitis showed decreases in arbor length in white matter astrocytes and reduced complexity in gray matter astrocytes compared to controls. These results provide the first evidence that innate immune activation of astrocytes is linked to altered cortical astrocyte morphology in SIV/HIV infection. Here, we demonstrate that astrocyte remodeling is correlated with infection. Perturbed neuron-glia signaling may be a driving factor in the development of HAND.
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Project description:In this study, we have uncovered novel proteolytic processing of the histone H3 tail in senescence models in primary fibroblasts and melanocytes. Cleavage of H3 tail occurs at two distinct residues and is mediated by Cathepsin L. We show that variant H3.3 is preferentially cleaved, and that cleaved histones are associated with chromatin and incorporated into nucleosomes. We also found that the histone chaperone ASF1a is required for chromatin incorporation of the cleaved histone species. Further, we show that overexpression of cleaved H3.3 induces a senescence program in fibroblasts in the absensence of oncogenic signaling. For the RNA-seq studies, growing IMR90 fibroblasts were compared to cells induced to senesce via oncogene activation or cleaved H3.3 overexpression. Growing controls consist of IMR90 cells infected with empty retroviral construct pBabe and grown under normal conditions for 13 days prior to RNA isolation. For oncogene-induced senescence samples, IMR90s carrying a tamoxifen-inducible H-RasV12 retroviral construct were induced to senesce by addition of 10nM tamoxifen to the media for 8 days. Finally, IMR90s were infected with a retroviral construct expressing the cleaved form of H3.3 with a C-terminal Flag tag. RNA samples form this group were isolated at days 3 (early) and 13 (late) post-infection. In all cases, total RNA samples were isolated using RNeasy kit (Qiagen) and prepared at the Icahn School of Medicine at Mount Sinai Genomics Core Facility for poly A library construction and sequencing on IlluminaHiSeq 2500.
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2023-10-25 | GSE241543 | GEO
Project description:Noncoding RNAs include small transcripts, such as microRNAs and piwi-interacting RNAs, and a wide range of long noncoding RNAs (lncRNAs). Although many lncRNAs have been identified, only a small number of lncRNAs have been characterized functionally. Here, we sought to identify lncRNAs differentially expressed during replicative senescence. We compared lncRNAs expressed in proliferating, early-passage, 'young' human diploid WI-38 fibroblasts [population doubling (PDL) 20] with those expressed in senescent, late-passage, 'old' fibroblasts (PDL 52) by RNA sequencing (RNA-Seq). Numerous transcripts in all lncRNA groups (antisense lncRNAs, pseudogene-encoded lncRNAs, previously described lncRNAs and novel lncRNAs) were validated using reverse transcription (RT) and real-time, quantitative (q)PCR. Among the novel senescence-associated lncRNAs (SAL-RNAs) showing lower abundance in senescent cells, SAL-RNA1 (XLOC_023166) was found to delay senescence, because reducing SAL-RNA1 levels enhanced the appearance of phenotypic traits of senescence, including an enlarged morphology, positive β-galactosidase activity, and heightened p53 levels. Our results reveal that the expression of known and novel lncRNAs changes with senescence and suggests that SAL-RNAs play direct regulatory roles in this important cellular process. RNA was extracted from both young and senescent WI-38 cells and used for total RNA-Seq.
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Project description:Tissue resident adult stem cells are known to participate in tissue regeneration and repair that follows cell turnover, or injury. It has been well established that aging impedes the regeneration capabilities at the cellular level, but it is not clear if the different onset of stem cell aging between individuals can be predicted or prevented at an earlier stage. Here we studied the dental pulp stem cells (DPSCs), a population of adult stem cells that is known to participate in the repair of an injured tooth, and its properties can be affected by aging. The dental pulp from third molars of a diverse patient group were surgically extracted, generating cells that had a high percentage of mesenchymal stem cell markers CD29, CD44, CD146 and Stro1 and had the ability to differentiate into osteo/odontogenic and adipogenic lineages. Through RNA seq and qPCR analysis we identified homeobox protein, Barx1, as a marker for DPSCs. Furthermore, using high throughput transcriptomic and proteomic analysis we identified markers for DPSC populations with accelerated replicative senescence. In particular, we show that the transforming growth factor-beta (TGF-β) pathway and the cytoskeletal proteins are upregulated in rapid aging DPSCs, indicating a loss of stem cell characteristics and spontaneous initiation of terminal differentiation. Importantly, using metabolic flux analysis, we identified a metabolic signature for the rapid aging DPSCs, prior to manifestation of senescence phenotypes. This metabolic signature therefore can be used to predict the onset of replicative senescence. Hence, the present study identifies Barx1 as a DPSCs marker and dissects the first predictive metabolic signature for DPSCs aging.
2019-11-12 | PXD011962 | Pride
Project description:Noncoding RNAs include small transcripts, such as microRNAs and piwi-interacting RNAs, and a wide range of long noncoding RNAs (lncRNAs). Although many lncRNAs have been identified, only a small number of lncRNAs have been characterized functionally. Here, we sought to identify lncRNAs differentially expressed during replicative senescence. We compared lncRNAs expressed in proliferating, early-passage, 'young' human diploid WI-38 fibroblasts [population doubling (PDL) 20] with those expressed in senescent, late-passage, 'old' fibroblasts (PDL 52) by RNA sequencing (RNA-Seq). Numerous transcripts in all lncRNA groups (antisense lncRNAs, pseudogene-encoded lncRNAs, previously described lncRNAs and novel lncRNAs) were validated using reverse transcription (RT) and real-time, quantitative (q)PCR. Among the novel senescence-associated lncRNAs (SAL-RNAs) showing lower abundance in senescent cells, SAL-RNA1 (XLOC_023166) was found to delay senescence, because reducing SAL-RNA1 levels enhanced the appearance of phenotypic traits of senescence, including an enlarged morphology, positive β-galactosidase activity, and heightened p53 levels. Our results reveal that the expression of known and novel lncRNAs changes with senescence and suggests that SAL-RNAs play direct regulatory roles in this important cellular process.
2016-02-08 | GSE77675 | GEO
Project description:BACKGROUND Acute myeloid leukemia (AML) is a highly heterogeneous disease. The predictive role of therapy-induced senescence (TIS) in cancer treatment in general and newly diagnosed (nd) AML patients in particular is undetermined. METHODS We established a flow cytometry-based senescence assay to detectsenescence in primary patient blasts to ex vivo chemotherapy (daunorubicin or cytarabine) in patients with newly diagnosed (nd) non-M3 AML. Bulk and single-cell analyses assessed gene expression and recurrent AML mutations. TIS-related gene signatures were interrogated in additional AML patient cohorts. Computational analyses, chromatin immunoprecipitation sequencing and other functional assays characterized TIS-related leukemia biology. RESULTS Ex vivo-determined TIS capacity predicted superior disease-free and overall survival in three independent cohorts comprising 92 patients with nd non-M3 AML across diverse (cyto-)genetic subgroups. Subsequent treatment with Bcl2 inhibitors venetoclax or navitoclax demonstrated their senescence-preferential killing. By interrogating 977 nd all-subtype AML patients from three additional independent cohorts, a TIS-derived gene classifier unexpectedly identified M3-AML/acute promyelocytic leukemia cases with very high accuracy in a PML-RARA-agnostic fashion. We found the polycomb-repressive complex 2 component Suz12 to regulate this classifier. Non-M3-AML cell lines in TIS differentiated upon all-trans retinoic acid (ATRA), or died in response to the Suz12-targeting histone deacetylase (HDAC) inhibitor panobinostat. CONCLUSIONS TIS predicts superior long-term outcome in nd AML and confers unifying plasticity across molecularly highly diverse AML subtypes towards an M3-like state, which enables consolidative senolysis by Bcl2 family or HDAC inhibition, or senodifferentiation by ATRA as novel plasticity-based treatment concepts.
2025-02-17 | GSE289427 | GEO