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Transcriptomic Analysis of Cellular Senescence: One Step Closer to Senescence Atlas.

ABSTRACT: Senescent cells that gradually accumulate during aging are one of the leading causes of aging. While senolytics can improve aging in humans as well as mice by specifically eliminating senescent cells, the effect of the senolytics varies in different cell types, suggesting variations in senescence. Various factors can induce cellular senescence, and the rate of accumulation of senescent cells differ depending on the organ. In addition, since the heterogeneity is due to the spatiotemporal context of senescent cells, in vivo studies are needed to increase the understanding of senescent cells. Since current methods are often unable to distinguish senescent cells from other cells, efforts are being made to find markers commonly expressed in senescent cells using bulk RNA-sequencing. Moreover, single-cell RNA (scRNA) sequencing, which analyzes the transcripts of each cell, has been utilized to understand the in vivo characteristics of the rare senescent cells. Recently, transcriptomic cell atlases for each organ using this technology have been published in various species. Novel senescent cells that do not express previously established marker genes have been discovered in some organs. However, there is still insufficient information on senescent cells due to the limited throughput of the scRNA sequencing technology. Therefore, it is necessary to improve the throughput of the scRNA sequencing technology or develop a way to enrich the rare senescent cells. The in vivo senescent cell atlas that is established using rapidly developing single-cell technologies will contribute to the precise rejuvenation by specifically removing senescent cells in each tissue and individual.

SUBMITTER: Kim S

PROVIDER: S-EPMC8019598 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe RNA modification 5-methylcytosine (m5C) is one of the most prevalent post-transcriptional modifications, with increasing evidence demonstrating its extensive involvement in the tumorigenesis and progression of various cancers. Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related deaths worldwide. However, the role of m5C modulators in shaping tumor microenvironment (TME) heterogeneity and regulating immune cell infiltration in CRC requires further clarification.ResultsThe transcriptomic sequencing data of 18 m5C regulators and clinical data of patients with CRC were obtained from The Cancer Genome Atlas (TCGA) and systematically evaluated. We found that 16 m5C regulators were differentially expressed between CRC and normal tissues. Unsupervised cluster analysis was then performed and revealed two distinct m5C modification patterns that yielded different clinical prognoses and biological functions in CRC. We demonstrated that the m5C score constructed from eight m5C-related genes showed excellent prognostic performance, with a subsequent independent analysis confirming its predictive ability in the CRC cohort. Then we developed a nomogram containing five clinical risk factors and the m5C risk score and found that the m5C score exhibited high prognostic prediction accuracy and favorable clinical applicability. Moreover, the CRC patients with low m5C score were characterized by "hot" TME exhibiting increased immune cell infiltration and higher immune checkpoint expression. These characteristics were highlighted as potential identifiers of suitable candidates for anticancer immunotherapy. Although the high m5C score represented the non-inflammatory phenotype, the CRC patients in this group exhibited high level of sensitivity to molecular-targeted therapy.ConclusionOur comprehensive analysis indicated that the novel m5C clusters and scoring system accurately reflected the distinct prognostic signature, clinicopathological characteristics, immunological phenotypes, and stratifying therapeutic opportunities of CRC. Our findings, therefore, offer valuable insights into factors that may be targeted in the development of precision medicine-based therapeutic strategies for CRC.