Sirt6-mediated epigenetic modification of DNA accessibility is essential for Pou2f3-induced thymic tuft cell development

• Published in: Communications biology Vol. 5; no. 1; p. 544
• Main Authors: Zhang, Qian, Zhang, Jiayu, Lei, Tong, Liang, Zhanfeng, Dong, Xue, Sun, Liguang, Zhao, Yong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.06.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 38/91; 45/23; 631/250/1620/1840; 631/250/2152/1566/2493; 82; 82/51; 96; 96/31; AIRE protein; Biology; Biomedical and Life Sciences; Chromatin; Epigenetics; Epithelial cells; Life Sciences; Lymphocytes T; Thymus
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03484-9

Thymic epithelial cells (TECs) are essential for the production of self-tolerant T cells. The newly identified thymic tuft cells are regulated by Pou2f3 and represent important elements for host type 2 immunity. However, epigenetic involvement in thymic tuft cell development remains unclear. We performed single-cell ATAC-seq of medullary TEC (mTEC) and established single-cell chromatin accessibility profiling of mTECs. The results showed that mTEC III cells can be further divided into three groups (Late Aire 1, 2, and 3) and that thymic tuft cells may be derived from Late Aire 2 cells. Pou2f3 is expressed in both Late Aire 2 cells and thymic tuft cells, while Pou2f3 -regulated genes are specifically expressed in thymic tuft cells with simultaneous opening of chromatin accessibility, indicating the involvement of epigenetic modification in this process. Using the epigenetic regulator Sirt6 -defect mouse model, we found that Sirt6 deletion increased Late Aire 2 cells and decreased thymic tuft cells and Late Aire 3 cells without affecting Pou2f3 expression. However, Sirt6 deletion reduced the chromatin accessibility of Pou2f3 -regulated genes in thymic tuft cells, which may be caused by Sirt6 –mediated regulation of Hdac9 expression. These data indicate that epigenetic regulation is indispensable for Pou2f3 -mediated thymic tuft cell development. Thymic epithelial cells (TECs) are essential for the production of self-tolerant T cells. Single-cell ATAC-seq of medullary TECs suggests that Sirt6-mediated epigenetic regulation may regulate the development of thymic tuft cells from these TECs.