4.5SH RNA counteracts deleterious exonization of SINE B1 in mice

Rei Yoshimoto; Yuta Nakayama; Ikuko Nomura; Ikuko Yamamoto; Yumeka Nakagawa; Shigeyuki Tanaka; Misuzu Kurihara; Yu Suzuki; Takehiko Kobayashi; Hiroko Kozuka-Hata; Masaaki Oyama; Mari Mito; Shintaro Iwasaki; Tomohiro Yamazaki; Tetsuro Hirose; Kimi Araki; Shinichi Nakagawa

doi:10.1016/j.molcel.2023.11.019

4.5SH RNA counteracts deleterious exonization of SINE B1 in mice

Mol Cell. 2023 Dec 21;83(24):4479-4493.e6. doi: 10.1016/j.molcel.2023.11.019. Epub 2023 Dec 13.

Authors

Rei Yoshimoto¹, Yuta Nakayama², Ikuko Nomura², Ikuko Yamamoto², Yumeka Nakagawa³, Shigeyuki Tanaka³, Misuzu Kurihara², Yu Suzuki⁴, Takehiko Kobayashi⁴, Hiroko Kozuka-Hata⁵, Masaaki Oyama⁵, Mari Mito⁶, Shintaro Iwasaki⁷, Tomohiro Yamazaki⁸, Tetsuro Hirose⁹, Kimi Araki¹⁰, Shinichi Nakagawa¹¹

Affiliations

¹ Department of Applied Biological Sciences, Faculty of Agriculture, Setsunan University, 45-1 Nagaotoge-cho, Hirakata City, Osaka 573-0101, Japan. Electronic address: rei.yoshimoto@setsunan.ac.jp.
² RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo Nishi 6-chome, Kita-ku, Sapporo 060-0812, Japan.
³ Department of Applied Biological Sciences, Faculty of Agriculture, Setsunan University, 45-1 Nagaotoge-cho, Hirakata City, Osaka 573-0101, Japan.
⁴ Laboratory of Genome Regeneration, Institute for Quantitative Biosciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
⁵ Medical Proteomics Laboratory, The Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
⁶ RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
⁷ RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba 277-8561, Japan.
⁸ RNA Biofunction Laboratory, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁹ RNA Biofunction Laboratory, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan; Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
¹⁰ Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan; Center for Metabolic Regulation of Healthy Aging, Kumamoto University, 1-1-1, Honjo, Kumamoto 860-8556, Japan.
¹¹ RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo Nishi 6-chome, Kita-ku, Sapporo 060-0812, Japan. Electronic address: nakagawas@pharm.hokudai.ac.jp.

PMID: 38096826
DOI: 10.1016/j.molcel.2023.11.019

Abstract

4.5SH RNA is a highly abundant, small rodent-specific noncoding RNA that localizes to nuclear speckles enriched in pre-mRNA-splicing regulators. To investigate the physiological functions of 4.5SH RNA, we have created mutant mice that lack the expression of 4.5SH RNA. The mutant mice exhibited embryonic lethality, suggesting that 4.5SH RNA is an essential species-specific noncoding RNA in mice. RNA-sequencing analyses revealed that 4.5SH RNA protects the transcriptome from abnormal exonizations of the antisense insertions of the retrotransposon SINE B1 (asB1), which would otherwise introduce deleterious premature stop codons or frameshift mutations. Mechanistically, 4.5SH RNA base pairs with complementary asB1-containing exons via the target recognition region and recruits effector proteins including Hnrnpm via its 5' stem loop region. The modular organization of 4.5SH RNA allows us to engineer a programmable splicing regulator to induce the skipping of target exons of interest. Our results also suggest the general existence of splicing regulatory noncoding RNAs.

Keywords: 4.5SH RNA; Hnrnpm; SINE B1; alternative splicing; exon skipping; noncoding RNA; retrotransposon.

MeSH terms

Alternative Splicing
Animals
Codon, Nonsense
Exons / genetics
Mice
RNA Splicing* / genetics
RNA, Small Untranslated*
Retroelements / genetics

Substances

RNA, Small Untranslated
Retroelements
Codon, Nonsense