Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cell Reports  

The senescent microenvironment and aged cells per se contribute to tissue remodeling, chronic inflammation, and age-associated dysfunction. However, the metabolic and epigenomic bases of the senescence-associated secretory phenotype (SASP) remain largely unknown. Here, we show that ATP-citrate lyase (ACLY), a key enzyme in acetyl-coenzyme A (CoA) synthesis, is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.

DOI： 10.1016/j.celrep.2024.114496

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Biological Chemistry  

RNA sequencing (RNA-seq) is a powerful technique for understanding cellular state and dynamics. However, comprehensive transcriptomic characterization of multiple RNA-seq datasets is laborious without bioinformatics training and skills. To remove the barriers to sequence data analysis in the research community, we have developed "RNAseqChef" (RNA-seq data controller highlighting expression features), a web-based platform of systematic transcriptome analysis that can automatically detect, integrate, and visualize differentially expressed genes and their biological functions. To validate its versatile performance, we examined the pharmacological action of sulforaphane (SFN), a natural isothiocyanate, on various types of cells and mouse tissues using multiple datasets in vitro and in vivo. Notably, SFN treatment upregulated the ATF6-mediated unfolded protein response in the liver and the NRF2-mediated antioxidant response in the skeletal muscle of diet-induced obese mice. In contrast, the commonly downregulated pathways included collagen synthesis and circadian rhythms in the tissues tested. On the server of RNAseqChef, we simply evaluated and visualized all analyzing data and discovered the NRF2-independent action of SFN. Collectively, RNAseqChef provides an easy-to-use open resource that identifies context-dependent transcriptomic features and standardizes data assessment.

DOI： 10.1016/j.jbc.2023.104810

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Macrophages are maintained by bone marrow (BM)–derived monocytes, but macrophages originating from fetal liver (FL) or yolk sac (YS) persist in many adult tissues due to their higher proliferative capacity. Here, we report useful models of macrophages with different origins. We expanded macrophages from mouse BM, FL, or YS through long-term culture. They proliferated with M-CSF, and YS lines were the fastest and survived without M-CSF for a longer period. YS and FL lines were more resistant to apoptotic cell death and similar in gene expression/chromatin accessibility, whereas YS and BM lines exhibited the most distinct profiles. When transplanted into mice, YS line expressed markers lost during the culture. BM, FL, and YS lines appear to maintain differences in intrinsic proliferation/anti-apoptosis/survival capacities and can restore phenotypes lost during the culture by in vivo transfer. Our models help in the understanding of physiological/pathological roles of macrophages with different origins.

DOI： 10.1016/j.isci.2025.112635

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.bneo.2024.100005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elife  

Skeletal muscle exhibits remarkable plasticity in response to environmental cues, with stress-dependent effects on the fast-twitch and slow-twitch fibers. Although stress-induced gene expression underlies environmental adaptation, it is unclear how transcriptional and epigenetic factors regulate fiber type-specific responses in the muscle. Here, we show that flavin-dependent lysine-specific demethylase-1 (LSD1) differentially controls responses to glucocorticoid and exercise in postnatal skeletal muscle. Using skeletal muscle-specific LSD1-knockout mice and in vitro approaches, we found that LSD1 loss exacerbated glucocorticoid-induced atrophy in the fast fiber-dominant muscles, with reduced nuclear retention of Foxk1, an anti-autophagic transcription factor. Furthermore, LSD1 depletion enhanced endurance exercise-induced hypertrophy in the slow fiber-dominant muscles, by induced expression of ERRγ, a transcription factor that promotes oxidative metabolism genes. Thus, LSD1 serves as an 'epigenetic barrier' that optimizes fiber type-specific responses and muscle mass under the stress conditions. Our results uncover that LSD1 modulators provide emerging therapeutic and preventive strategies against stress-induced myopathies such as sarcopenia, cachexia, and disuse atrophy.

DOI： 10.7554/eLife.84618

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Event date： 2024.11

Language：English   Presentation type：Oral presentation (general)  

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Event date： 2024.11

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2024.7

Language：Japanese   Presentation type：Poster presentation  

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Event date： 2024.6

Language：Japanese   Presentation type：Poster presentation  

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Event date： 2023.12

Language：Japanese   Presentation type：Oral presentation (general)  

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Language：Japanese   Publisher：医歯薬出版(株)  

Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

DOI： 10.18958/7323-00005-0000587-00

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Work type：Web Service  

遺伝子発現変動を自動的に可視化するRNA-seq統合解析ツール

DOI： 10.5281/zenodo.7095217

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Other Link： http://imeg-ku.shinyapps.io/RNAseqChef/

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