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2 results on '"Mika Nishio"'

1. Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment.

Author

Kenichi Miyata, Xiangyu Zhou, Mika Nishio, Aki Hanyu, Masatomo Chiba, Hiroko Kawasaki, Tomo Osako, Kengo Takeuchi, Shinji Ohno, Takayuki Ueno, Reo Maruyama, and Akiko Takahashi

Subjects
TUMOR microenvironment, GENE expression, CELLULAR aging, AGING, CHROMATIN, SPIDER silk
Abstract

Cellular senescence and senescence-associated secretory phenotype (SASP) in stromal cells within the tumor microenvironment promote cancer progression. Although cellular senescence has been shown to induce changes in the higher-order chromatin structure and abnormal transcription of repetitive elements in the genome, the functional significance of these changes is unclear. In this study, we examined the human satellite II (hSATII) loci in the pericentromere to understand these changes and their functional significance. Our results indicated that the hSATII loci decompact during senescence induction, resulting in new DNA-DNA interactions in distinct genomic regions, which we refer to as DRISR (Distinctive Regions Interacted with Satellite II in Replicative senescent Fibroblasts). Interestingly, decompaction occurs before the expression of hSATII RNA. The DRISR with altered chromatin accessibility was enriched for motifs associated with cellular senescence and inflammatory SASP genes. Moreover, DNA-fluorescence in situ hybridization analysis of the breast cancer tissues revealed hSATII decompaction in cancer and stromal cells. Furthermore, we reanalyzed the single-cell assay for transposase-accessible chromatin with sequencing data and found increased SASP-related gene expression in fibroblasts exhibiting hSATII decompaction in breast cancer tissues. These findings suggest that changes in the higher-order chromatin structure of the pericentromeric repetitive sequences during cellular senescence might directly contribute to the cellular senescence phenotype and cancer progression via inflammatory gene expression. [ABSTRACT FROM AUTHOR]

Published
2023
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2. Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer

Author

Akiko Takahashi, Koji Ueda, Risa Fujii, Yoshinori Imai, Eiji Hara, Toru Hirota, Katsuhiko Shirahige, Hideyuki Saya, Hao Zheng, Toyonori Sakata, Li Jiang, Mizuho Nakayama, Satoshi Nagayama, Ryosuke Kojima, Hiroyuki Seimiya, Masanobu Oshima, Tomoyoshi Nakadai, Liying Yang, Satoshi Hori, Ryo Okada, Tze Mun Loo, Shinya Toyokuni, Reo Maruyama, Mika Nishio, and Kenichi Miyata

Subjects
Senescence, Aging, RNA, Untranslated, senescence, Centromere, pericentromeric RNA, small extracellular vesicles, Biology, medicine.disease_cause, Mice, Transcription (biology), Neoplasms, Gene expression, medicine, Animals, Humans, Cellular Senescence, Inflammation, Mice, Inbred BALB C, Multidisciplinary, fungi, DNA, DNA, Neoplasm, Cell Biology, Biological Sciences, CTCF, Non-coding RNA, Phenotype, Cell biology, Chromatin, DNA-Binding Proteins, HEK293 Cells, Gene Expression Regulation, senescence-associated secretory phenotype, Female, Carcinogenesis, Protein Binding
Abstract

Significance During the aging process, senescent cells secrete inflammatory factors, causing various age-related pathologies. Thus, controlling the senescence-associated secretory phenotype (SASP) can tremendously benefit human health. Although SASP seems to be induced by the alteration of chromosomal organization, its underlying mechanism remains unclear. Here, it has been revealed that noncoding RNA (ncRNA) transcribed from pericentromeric repetitive elements impairs the DNA binding of CCCTC-binding factor, resulting in the alteration of chromosomal accessibility and the activation of SASP-like inflammatory genes. Notably, the ncRNA was transferred into surrounding cells via small extracellular vesicles, acting as a tumorigenic SASP factor. Our study highlights a novel mechanism regulating chromatin interaction and inflammatory gene expression in senescence and cancer., Cellular senescence causes a dramatic alteration of chromatin organization and changes the gene expression profile of proinflammatory factors, thereby contributing to various age-related pathologies through the senescence-associated secretory phenotype (SASP). Chromatin organization and global gene expression are maintained by the CCCTC-binding factor (CTCF); however, the molecular mechanism underlying CTCF regulation and its association with SASP gene expression remains unclear. We discovered that noncoding RNA (ncRNA) derived from normally silenced pericentromeric repetitive sequences directly impairs the DNA binding of CTCF. This CTCF disturbance increases the accessibility of chromatin and activates the transcription of SASP-like inflammatory genes, promoting malignant transformation. Notably, pericentromeric ncRNA was transferred into surrounding cells via small extracellular vesicles acting as a tumorigenic SASP factor. Because CTCF blocks the expression of pericentromeric ncRNA in young cells, the down-regulation of CTCF during cellular senescence triggers the up-regulation of this ncRNA and SASP-related inflammatory gene expression. In this study, we show that pericentromeric ncRNA provokes chromosomal alteration by inhibiting CTCF, leading to a SASP-like inflammatory response in a cell-autonomous and non–cell-autonomous manner and thus may contribute to the risk of tumorigenesis during aging.

Published
2021

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