美国德州农工大学Xiuren Zhang和华南师范大学张钟徽共同合作，近期取得重要工作进展。他们研究提出，SERRATE驱动相分离以调控m⁶A修饰和miRNA生物发生。相关研究成果2024年10月29日在线发表于《自然—细胞生物学》杂志上。

据介绍，甲基转移酶复合物（MTC）将N6腺苷（m⁶A）沉积在RNA上，而微处理器产生microRNA。这两种不同的复合物是否以及如何相互交叉调节的研究很少。

研究人员发现，MTC亚基B倾向于形成活性较差的不溶性缩合物，其水平由20S蛋白酶体监测。相反，微处理器组件SERRATE（SE）形成液体状冷凝物，这反过来又促进了MTC亚基B的溶解度和稳定性，导致MTC活性增加。

与此一致的是，表达SE变体的低功能性品系（这些变体在与MTC相互作用或液滴状相行为上存在缺陷）表现出较低的m⁶A水平。相应地，MTC可以将微处理器招募到MIRNA位点，促进主要miRNA底物的共转录切割。

此外，在单链基底区携带m⁶A修饰的初级miRNA底物被m⁶A识别蛋白富集，这些蛋白将微处理器保留在核质中以继续处理。

总之，这一研究揭示了通过MTC和微处理器协调在RNA修饰和加工中的相分离机制。

附：英文原文

Title: SERRATE drives phase separation behaviours to regulate m6A modification and miRNA biogenesis

Author: Zhong, Songxiao, Li, Xindi, Li, Changhao, Bai, Haiyan, Chen, Jingjing, Gan, Lu, Zhu, Jiyun, Oh, Taerin, Yan, Xingxing, Zhu, Jiaying, Li, Niankui, Koiwa, Hisashi, Meek, Thomas, Peng, Xu, Yu, Bin, Zhang, Zhonghui, Zhang, Xiuren

Issue&Volume: 2024-10-29

Abstract: The methyltransferase complex (MTC) deposits N6-adenosine (m6A) onto RNA, whereas the microprocessor produces microRNA. Whether and how these two distinct complexes cross-regulate each other has been poorly studied. Here we report that the MTC subunit B tends to form insoluble condensates with poor activity, with its level monitored by the 20S proteasome. Conversely, the microprocessor component SERRATE (SE) forms liquid-like condensates, which in turn promote the solubility and stability of the MTC subunit B, leading to increased MTC activity. Consistently, the hypomorphic lines expressing SE variants, defective in MTC interaction or liquid-like phase behaviour, exhibit reduced m6A levels. Reciprocally, MTC can recruit the microprocessor to the MIRNA loci, prompting co-transcriptional cleavage of primary miRNA substrates. Additionally, primary miRNA substrates carrying m6A modifications at their single-stranded basal regions are enriched by m6A readers, which retain the microprocessor in the nucleoplasm for continuing processing. This reveals an unappreciated mechanism of phase separation in RNA modification and processing through MTC and microprocessor coordination.

DOI: 10.1038/s41556-024-01530-8

Source: https://www.nature.com/articles/s41556-024-01530-8