环状 RNA circTmem241 通过启动 Elk3 转录驱动 III 型固有淋巴细胞分化。
Circular RNA circTmem241 drives group III innate lymphoid cell differentiation via initiation of Elk3 transcription.
机构信息
Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
出版信息
Nat Commun. 2022 Aug 11;13(1):4711. doi: 10.1038/s41467-022-32322-z.
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, circTmem241Elk3 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，ILC 谱系特化是如何调节的在很大程度上仍不清楚。在这里，我们发现 circTmem241 在第三类先天淋巴细胞 (ILC3)及其祖细胞中高度表达。circTmem241 缺失会损害 ILC3 的定型，并减弱抗细菌免疫。在机制上，circTmem241 与 Nono 蛋白相互作用，将组蛋白甲基转移酶 Ash1l 招募到 ILC 祖细胞 (ILCP) 中的 Elk3 启动子上。Ash1l 在 Elk3 启动子上对组蛋白的修饰增强了染色质的可及性，从而启动 Elk3 转录。值得注意的是，circTmem241、Nono 和 Ash1l ILCPs 的 ILC3 分化受损，而 Elk3 的过表达可挽救 ILC3 定型能力。最后，circTmem241Elk3 小鼠中 ILC3 的数量减少，对细菌感染更敏感。我们揭示了 circTmem241-Nono-Ash1l-Elk3 轴对于 ILCP 分化为 ILC3P 和 ILC3 成熟是必需的，这对于操纵该轴以治疗感染性疾病中的 ILC 发育很重要。
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