Role of PRC2 in the stochastic expression of Aire target genes and development of mimetic cells in the thymus.

IF 10.6 1区 医学 Q1 IMMUNOLOGY
Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-04-17 DOI:10.1084/jem.20240817
Minoru Matsumoto, Masaki Yoshida, Takeshi Oya, Koichi Tsuneyama, Mitsuru Matsumoto, Hideyuki Yoshida
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引用次数: 0

Abstract

The transcriptional targets of Aire and the mechanisms controlling their expression in medullary thymic epithelial cells (mTECs) need to be clarified to understand Aire's tolerogenic function. By using a multi-omics single-cell approach coupled with deep scRNA-seq, we examined how Aire controls the transcription of a wide variety of genes in a small fraction of Aire-expressing cells. We found that chromatin repression by PRC2 is an important step for Aire to achieve stochastic gene expression. Aire unleashed the silenced chromatin configuration caused by PRC2, thereby increasing the expression of its functional targets. Besides this preconditioning for Aire's gene induction, we demonstrated that PRC2 also controls the composition of mTECs that mimic the developmental trait of peripheral tissues, i.e., mimetic cells. Of note, this action of PRC2 was independent of Aire and it was more apparent than Aire. Thus, our study uncovered the essential role of polycomb complex for Aire-mediated promiscuous gene expression and the development of mimetic cells.

PRC2在胸腺Aire靶基因的随机表达和模拟细胞发育中的作用。
Aire的转录靶点及其在胸腺髓上皮细胞(mTECs)中的表达调控机制需要明确,以了解Aire的耐受原功能。通过使用多组学单细胞方法结合深度scRNA-seq,我们研究了Aire如何在一小部分表达Aire的细胞中控制多种基因的转录。我们发现PRC2的染色质抑制是Aire实现随机基因表达的重要步骤。Aire释放了由PRC2引起的沉默染色质结构,从而增加了其功能靶点的表达。除了Aire基因诱导的这种预处理外,我们还证明PRC2还控制模拟外周组织(即模拟细胞)发育性状的mtec的组成。值得注意的是,PRC2的这种作用不依赖于Aire,而且比Aire更为明显。因此,我们的研究揭示了多梳复合体在空气介导的混杂基因表达和模拟细胞发育中的重要作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
26.60
自引率
1.30%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.
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