m6A modification of HSATIII lncRNAs regulates temperature‐dependent splicing

• Published in: The EMBO journal Vol. 40; no. 15
• Main Authors: Ninomiya, Kensuke, Iwakiri, Junichi, Aly, Mahmoud Khamis, Sakaguchi, Yuriko, Adachi, Shungo, Natsume, Tohru, Terai, Goro, Asai, Kiyoshi, Suzuki, Tsutomu, Hirose, Tetsuro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.08.2021; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Adenosine; EMBO09; EMBO36; Introns; Kinases; long noncoding RNA; m6A modification; molecular sponge; N6-methyladenosine; nuclear stress bodies; Nucleotide sequence; Organelles; Phosphorylation; pre‐mRNA splicing; Proteins; Recovery; Retention; RNA modification; Splicing; Splicing factors; Temperature dependence; Temperature effects; Thermal stress; long noncoding RNA; pre‐mRNA splicing; A modification; nuclear stress bodies; m; molecular sponge
• DOI: 10.15252/embj.2021107976
• ISSN: 0261-4189

Nuclear stress bodies (nSBs) are nuclear membraneless organelles formed around stress‐inducible HSATIII architectural long noncoding RNAs (lncRNAs). nSBs repress splicing of hundreds of introns during thermal stress recovery, which are partly regulated by CLK1 kinase phosphorylation of temperature‐dependent Ser/Arg‐rich splicing factors (SRSFs). Here, we report a distinct mechanism for this splicing repression through protein sequestration by nSBs. Comprehensive identification of RNA‐binding proteins revealed HSATIII association with proteins related to N 6 ‐methyladenosine (m 6 A) RNA modification. 11% of the first adenosine in the repetitive HSATIII sequence were m 6 A‐modified. nSBs sequester the m 6 A writer complex to methylate HSATIII, leading to subsequent sequestration of the nuclear m 6 A reader, YTHDC1. Sequestration of these factors from the nucleoplasm represses m 6 A modification of pre‐mRNAs, leading to repression of m 6 A‐dependent splicing during stress recovery phase. Thus, nSBs serve as a common platform for regulation of temperature‐dependent splicing through dual mechanisms employing two distinct ribonucleoprotein modules with partially m 6 A‐modified architectural lncRNAs. SYNOPSIS Nuclear stress bodies (nSBs) form around stress‐inducible HSATIII lncRNAs and repress splicing of hundreds of introns during and after thermal stress. Here, HSATIII m 6 A‐modification is found to sequester YTHDC1 in nSBs during thermal stress recovery, thereby repressing m 6 A‐dependent splicing of pre‐mRNAs in the nucleoplasm. HSATIII architectural lncRNAs are m 6 A‐modified. The m 6 A‐writer complex components and the nuclear m 6 A‐reader protein YTHDC1 are localized in nSBs during thermal stress recovery. YTHDC1 sequestration by nSBs promotes temperature‐dependent intron retention of the target pre‐mRNAs. nSBs promote intron retention during thermal stress recovery through two distinct mechanisms: YTHDC1 sequestration and the recently reported SRSF9 phosphorylation. Graphical Abstract During thermal stress recovery sequestration of m 6 A writer complex components and YTHDF1 in nuclear stress bodies promotes temperature‐dependent intron retention of target pre‐mRNAs.