胸腺上皮细胞放大表观遗传噪声以促进免疫耐受，这一成果由芝加哥大学Andrew S. Koh小组经过不懈努力而取得。该项研究成果发表在2025年8月20日出版的《自然》上。

该研究组以胸腺上皮细胞的体细胞可塑性为主题，这有助于选择自我区分的T细胞库，作为生理模型系统，表明在胸腺上皮成熟过程中，核小体密集区域背景染色质可及性的波动被放大，从而导致限制在其他特化细胞类型的基因的异位表达。这种染色质不稳定不依赖于AIRE诱导的转录，但在此之前会抑制肿瘤抑制因子p53。增强p53活性间接稳定了染色质，抑制了异位转录，限制了细胞可塑性，并引导了多器官自身免疫。染色质可及性噪声升高的基因组区域选择性富集核小体不稳定聚合AT束，并与基线DNA损伤和转录起始升高相关。综上所述，他们的发现定义了调节细胞命运完整性的分子杠杆，并以胸腺上皮细胞为主题进行免疫耐受。

据介绍，细胞可塑性是脊椎动物适应、组织修复和肿瘤发生的主要特征。然而，调节体细胞命运稳定性的机制尚不清楚。

附：英文原文

Title: Thymic epithelial cells amplify epigenetic noise to promote immune tolerance

Author: Gamble, Noah, Caldwell, Jason A., McKeever, Joshua, Kaiser, Caroline, Bradu, Alexandra, Dooley, Peyton J., Klemm, Sandy, Greenleaf, William J., Hibino, Narutoshi, Dinner, Aaron R., Koh, Andrew S.

Issue&Volume: 2025-08-20

Abstract: Cellular plasticity is a principal feature of vertebrate adaptation, tissue repair and tumorigenesis1,2. However, the mechanisms that regulate the stability of somatic cell fates remain unclear. Here, we use the somatic plasticity of thymic epithelial cells, which facilitates the selection of a self-discriminating T cell repertoire3, as a physiological model system to show that fluctuations in background chromatin accessibility in nucleosome-dense regions are amplified during thymic epithelial maturation for the ectopic expression of genes restricted to other specialized cell types. This chromatin destabilization was not dependent on AIRE-induced transcription but was preceded by repression of the tumour suppressor p53. Augmenting p53 activity indirectly stabilized chromatin, inhibited ectopic transcription, limited cellular plasticity and caused multi-organ autoimmunity. Genomic regions with heightened chromatin accessibility noise were selectively enriched for nucleosome-destabilizing polymeric AT tracts and were associated with elevated baseline DNA damage and transcriptional initiation. Taken together, our findings define molecular levers that modulate cell fate integrity and are used by thymic epithelial cells for immunological tolerance.

DOI: 10.1038/s41586-025-09424-x

Source: https://www.nature.com/articles/s41586-025-09424-x