scholarly journals LncRNA GUARDIN suppresses cellular senescence through a LRP130-PGC1α-FOXO4-p21-dependent signaling axis

2019 ◽  
Author(s):  
Xuedan Sun ◽  
Rick FrancisThorne ◽  
Xu Dong Zhang ◽  
Miao He ◽  
Shanshan Feng ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cellular Senescence ◽  
Genome Stability ◽  
Transcriptional Repressor ◽  
Cell Fate Decisions ◽  
Non Coding Rna ◽  
Repressor Complex ◽  
Signaling Axis ◽  
Molecular Signals ◽  
Long Non Coding Rna

AbstractThe long non-coding RNA GUARDIN functions to protect genome stability. Inhibiting GUARDIN expression can alter cell fate decisions towards senescence or apoptosis, but the underlying molecular signals are unknown. Here we show that GUARDIN is an essential component of a transcriptional repressor complex involving LRP130 and PGC1α which suppresses FOXO4 expression. GUARDIN acts as a scaffold to stabilize LRP130/PGC1α heterodimers and their occupancy at the FOXO4 promotor. Destabilizing this complex by silencing of GUARDIN, LRP130 or PGC1α leads to FOXO4-dependent upregulation of p21, thereby driving cells into senescence. We also found that GUARDIN expression was induced by rapamycin, a senolytic agent that suppresses cell senescence. FOS-Like Antigen 2 (FOSL2) acts as a transcriptional repressor of GUARDIN with increased levels in the presence of rapamycin resulting from downregulation of FOSL2. Together, these results demonstrate that GUARDIN inhibits p21-dependent senescence through a LRP130-PGC1α-FOXO4 signaling axis and moreover, GUARDIN contributes to the anti-senolytic activities of rapamycin.

scholarly journals An Evolving Role for the Long Non-Coding RNA H19 in Aging and Senescence

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 563-563
Author(s):  
Christian Sell ◽  
Manali Potnis
Keyword(s):  
Cell Cycle ◽  
Somatic Cell ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Adult Stem Cells ◽  
Somatic Cells ◽  
Gene Transcript ◽  
Cell Fate Decisions ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Abstract The long non-coding RNA (lncRNA) H19 is a maternally imprinted gene transcript that, in conjunction with the neighboring Igf2 gene, is critical in controlling embryonic growth. Loss of H19 results in fetal overgrowth associated with Beckwith Weidemann syndrome, while elevated H19 occurs in human cancers. In the adult, H19 functions in cancer cells where it promotes migration and is correlated with poor prognosis, and in adult stem cells where it is a key regulator of cell fate decisions during differentiation. While the function of H19 in primary somatic cells has not been defined, a reduction in the abundance of H19 has been reported during senescence in endothelial cells. Given the critical importance of H19 in cell fate decisions, it is likely that understanding the precise function of H19 in somatic cells in general and why reduced levels occur with cellular senescence will provide novel insights into both somatic cell maintenance and the senescence program. Towards this end, we examined the role of H19 in somatic cell growth using cardiac interstitial fibroblasts. Our results indicate that H19 is not only vital for somatic cell proliferation and survival, but that depletion of H19 leads to cell cycle arrest and the formation of abnormal nuclei resulting in senescent cells. We are defining both the upstream regulators of H19 and the downstream mediators of senescence following H19 depletion. Overall, these results indicate an essential role for H19 in cell cycle progression, chromatin structure, and possibly proper mitotic division.

scholarly journals DNA damage dependent hypomethylation regulates the pro-angiogenic LncRNA MEG9

2018 ◽  
Author(s):  
Cristina Espinosa-Diez ◽  
RaeAnna Wilson ◽  
Rishima Mukherjee ◽  
Marlee Feltham ◽  
Clayton Hudson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Cell Fate ◽  
Genotoxic Stress ◽  
Loss Of Function ◽  
Fibrin Gel ◽  
Cell Fate Decisions ◽  
Angiogenesis Assay ◽  
Non Coding Rna ◽  
Long Non Coding Rna

AbstractChanges in gene expression are key for the cells to adapt and response to intrinsic and extrinsic stimulus. It has been shown that genotoxic stress induces global hypomethylation as a result of decreased expression of DNA methyl transferases (DNMT). We hypothesized that DNA damage suppresses long non-coding RNA expression in the vasculature via DNA methylation leading to more robust DNA repair/survival or cellular senescence/death cell fate decisions. We show here that ionizing radiation reduces the expression of DNMTs in the vascular endothelium and this leads to increased expression of the anti-apoptotic lncRNA MEG9. MEG9 is a lncRNA from the DLK1-DIO3 ncRNA cluster. Loss-of-function studies using RNA gapmers indicate that MEG9 protects endothelial cells from DNA damage induced cell death. Consistent with this phenotype, knockdown of MEG9 decreases growth factor dependent angiogenesis in a 3D fibrin gel angiogenesis assay. Mechanistically, we observed that MEG9 knockdown decreased the expression of cell survival genes including survivin and induced the expression of pro-apoptotic genes such as Bad/Bax. Taken together, our findings illustrate how DNA methylation at selective lncRNA loci can regulate their expression and drive endothelial cell fate decisions.

scholarly journals Fatty Acids Metabolism: The Bridge Between Ferroptosis and Ionizing Radiation

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhu-hui Yuan ◽  
Tong Liu ◽  
Hao Wang ◽  
Li-xiang Xue ◽  
Jun-jie Wang
Keyword(s):  
Fatty Acids ◽  
Cell Death ◽  
Ionizing Radiation ◽  
Cell Fate ◽  
Tumor Response ◽  
Cell Fate Decisions ◽  
Current Review ◽  
Pathway Crosstalk ◽  
Fatty Acids Metabolism ◽  
Molecular Signals

Exposure of tumor cells to ionizing radiation (IR) alters the microenvironment, particularly the fatty acid (FA) profile and activity. Moreover, abnormal FA metabolism, either catabolism or anabolism, is essential for synthesizing biological membranes and delivering molecular signals to induce ferroptotic cell death. The current review focuses on the bistable regulation characteristics of FA metabolism and explains how FA catabolism and anabolism pathway crosstalk harmonize different ionizing radiation-regulated ferroptosis responses, resulting in pivotal cell fate decisions. In summary, targeting key molecules involved in lipid metabolism and ferroptosis may amplify the tumor response to IR.

scholarly journals Cellular senescence in hepatocellular carcinoma induced by a long non-coding RNA-encoded peptide PINT87aa by blocking FOXM1-mediated PHB2

Theranostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 4929-4944
Author(s):  
Xiaohong Xiang ◽  
Yunong Fu ◽  
Kun Zhao ◽  
Runchen Miao ◽  
Xing Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cellular Senescence ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Regulation of bone marrow mesenchymal stem cell fate by long non-coding RNA

Bone ◽  
2020 ◽  
Vol 141 ◽  
pp. 115617
Author(s):  
Qiaoyue Guo ◽  
Qi Guo ◽  
Ye Xiao ◽  
Changjun Li ◽  
Yan Huang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cell Fate ◽  
Stem Cell Fate ◽  
Non Coding Rna ◽  
Long Non Coding Rna

scholarly journals Collective MAPK Signaling Dynamics Coordinates Epithelial Homeostasis

2019 ◽  
Author(s):  
Timothy J. Aikin ◽  
Amy F. Peterson ◽  
Michael J. Pokrass ◽  
Helen R. Clark ◽  
Sergi Regot
Keyword(s):  
Cell Fate ◽  
Temporal Patterns ◽  
Mapk Signaling ◽  
Paracrine Signaling ◽  
Cell Behaviors ◽  
Cell Fate Decisions ◽  
Epithelial Tissues ◽  
Mapk Activity ◽  
Signaling Axis ◽  
Quality Control Mechanism

ABSTRACTEpithelial tissues are constantly challenged by individual cell fate decisions while maintaining barrier function. During oncogenesis, mutant and normal cells also differ in their signaling states and cellular behaviors creating competitive interactions that are poorly understood. Here we show that the temporal patterns of MAPK activity are decoded by the ADAM17-EGFR paracrine signaling axis to coordinate migration of neighboring cells and promote extrusion of aberrantly-signaling cells. Concurrently, neighboring cells increase proliferation to maintain cell density while oncogene expressing cells undergo cell cycle arrest. Moreover, the stress MAPK p38 elicits the same paracrine signaling and extrusion response, suggesting that the ADAM17-EGFR pathway constitutes a quality control mechanism to eliminate and replace unfit cells from epithelial tissues. Overall, we show that the temporal patterns of MAPK activity coordinates both single and collective cell behaviors to maintain tissue homeostasis.

scholarly journals Long Non-coding RNA T-uc.189 Modulates Neural Progenitor Cell Fate by Regulating Srsf3 During Mouse Cerebral Cortex Development

2021 ◽  
Vol 15 ◽  
Author(s):  
Meng Zhang ◽  
Junjie Zhou ◽  
Li Jiao ◽  
Longjiang Xu ◽  
Lin Hou ◽  
...  
Keyword(s):  
Cell Fate ◽  
Ventricular Zone ◽  
Neural Progenitor Cell ◽  
Temporal Gene Expression ◽  
Non Coding Rna ◽  
Complex Process ◽  
Mouse Cerebral Cortex ◽  
Full Length Sequence ◽  
Long Non Coding Rna ◽  
The Brain

Neurogenesis is a complex process that depends on the delicate regulation of spatial and temporal gene expression. In our previous study, we found that transcribed ultra-conserved regions (T-UCRs), a class of long non-coding RNAs that contain UCRs, are expressed in the developing nervous systems of mice, rhesus monkeys, and humans. In this study, we first detected the full-length sequence of T-uc.189, revealing that it was mainly concentrated in the ventricular zone (VZ) and that its expression decreased as the brain matured. Moreover, we demonstrated that knockdown of T-uc.189 inhibited neurogenesis. In addition, we found that T-uc.189 positively regulated the expression of serine-arginine-rich splicing factor 3 (Srsf3). Taken together, our results are the first to demonstrate that T-uc.189 regulates the expression of Srsf3 to maintain normal neurogenesis during cortical development.

Genome Instability-related Long Non-coding RNA in Clear Renal Cell Carcinoma Determined using Computational Biology

2021 ◽  
Author(s):  
Yutao Wang ◽  
Kexin Yan ◽  
Jianbin Bi
Keyword(s):  
Renal Cell Carcinoma ◽  
Computational Biology ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Genome Stability ◽  
Clear Cell ◽  
Genome Instability ◽  
Cell Renal Cell Carcinoma ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Abstract There is evidence that long non-coding RNA (lncRNA) is related to genetic stability. However, the complex biological functions of these lncRNAs are unclear. In the present study, we applied computational biology to identify genome-related long noncoding RNA and identified 26 novel genomic instability-associated lncRNAs in clear cell renal cell carcinoma. We identified a genome instability-derived six lncRNA-based gene signature that significantly divided clear renal cell samples into high-and low-risk groups. We validated it in test cohorts. Based on the above analysis, we identified six lncRNAs related to clear cell carcinoma outcomes and genome stability based on computational biology. To further elucidate the role of the six lncRNAs in the model's genome stability, we performed a gene set variation analysis (GSVA) on the matrix. We performed Pearson correlation analysis between the GSVA scores of genomic stability-related pathways and lncRNA. It was determined that LINC00460 and LINC01234 could be used as critical factors in this study. They may influence the genome stability of clear cell carcinoma by participating in mediating critical targets in the base excision repair pathway, the DNA replication pathway, homologous recombination, mismatch repair pathway, and the P53 signaling pathway. These data suggest that LINC00460 and LINC01234 are crucial for the stability of the clear cell renal cell carcinoma genome.

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