Innate lymphoid cells (ILCs) exert important roles in host defense, tissue repair and inflammatory diseases. However, how ILC lineage specification is regulated remains largely elusive. Here we identify that circular RNA circTmem241 is highly expressed in group III innate lymphoid cells (ILC3s) and their progenitor cells. CircTmem241 deficiency impairs ILC3 commitment and attenuates anti-bacterial immunity. Mechanistically, circTmem241 interacts with Nono protein to recruit histone methyltransferase Ash1l onto Elk3 promoter in ILC progenitor cells (ILCPs). Ash1l-mediated histone modifications on Elk3 promoter enhance chromatin accessibility to initiate Elk3 transcription. Of note, circTmem241^−/−, Nono^−/− and Ash1l^−/− ILCPs display impaired ILC3 differentiation, while Elk3 overexpression rescues ILC3 commitment ability. Finally, circTmem241^−/−Elk3^−/− mice show lower numbers of ILC3s and are more susceptible to bacterial infection. We reveal that the circTmem241-Nono-Ash1l-Elk3 axis is required for the ILCP differentiation into ILC3P and ILC3 maturation, which is important to manipulate this axis for ILC development on treatment of infectious diseases.

先天淋巴细胞 (ILC) 在宿主防御、组织修复和炎症性疾病中发挥重要作用。然而，如何调节 ILC 谱系规范仍然难以捉摸。在这里，我们发现环状 RNA circTmem241在 III 组先天淋巴细胞 (ILC3s) 及其祖细胞中高度表达。CircTmem241缺乏会损害 ILC3 承诺并减弱抗菌免疫。从机制上讲，circTmem241与 Nono 蛋白相互作用，将组蛋白甲基转移酶 Ash1l 募集到ILC 祖细胞 (ILCP) 中的Elk3启动子上。Ash1l 介导的Elk3启动子上的组蛋白修饰增强了染色质的可及性以启动Elk3转录。值得注意的是，circTmem241 ^-/-、Nono ^-/-和Ash1l ^-/- ILCP 显示 ILC3 分化受损，而 Elk3 过表达挽救 ILC3 承诺能力。最后，circTmem241 ^-/- Elk3 ^-/-小鼠的 ILC3 数量较少，更容易受到细菌感染。我们揭示了circTmem241 -Nono-Ash1l-Elk3 轴是 ILCP 分化为 ILC3P 和 ILC3 成熟所必需的，这对于操纵该轴对于 ILC 发展以治疗传染病很重要。