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

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

doi:10.1038/s41556-024-01530-8

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

Nat Cell Biol. 2024 Oct 29. doi: 10.1038/s41556-024-01530-8. Online ahead of print.

Authors

Songxiao Zhong¹, Xindi Li¹, Changhao Li¹, Haiyan Bai², Jingjing Chen², Lu Gan^{3

4}, Jiyun Zhu¹, Taerin Oh¹, Xingxing Yan¹, Jiaying Zhu¹, Niankui Li¹, Hisashi Koiwa⁵, Thomas Meek¹, Xu Peng⁶, Bin Yu³, Zhonghui Zhang⁷, Xiuren Zhang^{8

9}

Affiliations

¹ Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
² Guangdong Provincial Key Laboratory of Biotechnology for Plant Development, School of Life Science, South China Normal University, Guangzhou, China.
³ School of Biological Sciences and Center for Plant Science Innovation, University of Nebraska-Lincoln, Lincoln, NE, USA.
⁴ Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China.
⁵ Department of Horticulture, Texas A&M University, College Station, TX, USA.
⁶ Department of Medical Physiology, College of Medicine, Texas A&M University, College Station, TX, USA.
⁷ Guangdong Provincial Key Laboratory of Biotechnology for Plant Development, School of Life Science, South China Normal University, Guangzhou, China. zhzhang@m.scnu.edu.cn.
⁸ Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA. xiuren.zhang@tamu.edu.
⁹ Department of Biology, Texas A&M University, College Station, TX, USA. xiuren.zhang@tamu.edu.

PMID: 39472512
DOI: 10.1038/s41556-024-01530-8

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.

Abstract

Grants and funding