Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong Special Administrative Region, China.
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO, USA.
EMBO J. 2024 Apr;43(8):1570-1590. doi: 10.1038/s44318-024-00074-9. Epub 2024 Mar 18.
Ten-eleven translocation (TET) proteins are dioxygenases that convert 5-methylcytosine (5mC) into 5-hydroxylmethylcytosine (5hmC) in DNA and RNA. However, their involvement in adult stem cell regulation remains unclear. Here, we identify a novel enzymatic activity-independent function of Tet in the Drosophila germline stem cell (GSC) niche. Tet activates the expression of Dpp, the fly homologue of BMP, in the ovary stem cell niche, thereby controlling GSC self-renewal. Depletion of Tet disrupts Dpp production, leading to premature GSC loss. Strikingly, both wild-type and enzyme-dead mutant Tet proteins rescue defective BMP signaling and GSC loss when expressed in the niche. Mechanistically, Tet interacts directly with Bap55 and Stat92E, facilitating recruitment of the Polybromo Brahma associated protein (PBAP) complex to the dpp enhancer and activating Dpp expression. Furthermore, human TET3 can effectively substitute for Drosophila Tet in the niche to support BMP signaling and GSC self-renewal. Our findings highlight a conserved novel catalytic activity-independent role of Tet as a scaffold protein in supporting niche signaling for adult stem cell self-renewal.
十 - 十一易位（TET）蛋白是双加氧酶，可将 DNA 和 RNA 中的 5-甲基胞嘧啶（5mC）转化为 5-羟甲基胞嘧啶（5hmC）。然而，它们在成人干细胞调节中的作用仍不清楚。在这里，我们确定了 Tet 在果蝇生殖干细胞（GSC）巢中的一种新的酶活性非依赖性功能。Tet 在卵巢干细胞巢中激活了 Dpp 的表达，Dpp 是 BMP 的果蝇同源物，从而控制 GSC 的自我更新。Tet 的耗竭会破坏 Dpp 的产生，导致 GSC 的过早丢失。引人注目的是，当在巢中表达时，野生型和酶失活突变 Tet 蛋白都可以挽救有缺陷的 BMP 信号和 GSC 丢失。在机制上，Tet 直接与 Bap55 和 Stat92E 相互作用，促进多溴素结合蛋白（PBAP）复合物募集到 dpp 增强子并激活 Dpp 的表达。此外，人源 TET3 可以有效地替代果蝇 Tet 在巢中支持 BMP 信号和 GSC 自我更新。我们的发现强调了 Tet 作为支架蛋白在支持成人干细胞自我更新的巢信号中的保守的新型催化活性非依赖性作用。
