Matsumoto Minoru, Yoshida Masaki, Oya Takeshi, Tsuneyama Koichi, Matsumoto Mitsuru, Yoshida Hideyuki
Department of Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
YCI Laboratory for Immunological Transcriptomics, RIKEN Center for Integrative Medical Science , Yokohama, Japan.
J Exp Med. 2025 Jul 7;222(7). doi: 10.1084/jem.20240817. Epub 2025 Apr 17.
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.
为了解Aire的致耐受性功能，需要阐明Aire的转录靶点及其在髓质胸腺上皮细胞（mTECs）中表达的调控机制。通过使用多组学单细胞方法结合深度单细胞RNA测序（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介导的染色质抑制是Aire实现随机基因表达的重要步骤。Aire解除了由PRC2引起的沉默染色质构型，从而增加了其功能靶点的表达。除了这种对Aire基因诱导的预处理外，我们还证明PRC2还控制着模仿外周组织发育特征的mTECs的组成，即模拟细胞。值得注意的是，PRC2的这一作用独立于Aire，且比Aire更明显。因此，我们的研究揭示了多梳复合物在Aire介导的杂乱基因表达和模拟细胞发育中的重要作用。
