遺伝子発現の新たな制御因子の同定～m3 C 修飾のポリ(A)RNA 中での機能を発見～

2025-11-04

2025-10-31 東京大学,旭川医科大学

東京大学と旭川医科大学の共同研究チームは、RNA修飾の一種である3-メチルシチジン(m3C)修飾の生体機能を初めて明らかにした。m3C修飾を導入する酵素METTL2Aが膵がん組織で高発現しており、予後不良やがん細胞増殖促進と関連することを発見。ダイレクトRNAシーケンシングにより、ポリ(A)RNA中のm3C修飾が主にコード配列のCCモチーフに集中し、遺伝子発現制御に関与することを示した。METTL2A抑制により標的RNAの発現量が増加するなど、m3C修飾が発現抑制的に働くことを実証。この成果は、RNA修飾を標的とした新しい創薬・がん治療法の開発に道を開くものである。

ダイレクト RNA シーケンシング法による、ポリ(A)RNA 中での m3 C 修飾の分布と遺伝子発現制御機能の解明

<関連情報>

ナノポア直接RNAシークエンシングにより、METTL2Aを介したポリ(A)RNA中のm3C部位が明らかに Nanopore direct RNA sequencing reveals METTL2A-mediated m3C sites in poly(A) RNA

Shuhei Mitsutomi,Anzu Sugawara,Masahide Seki,Yutaka Suzuki,Sotaro Miyao,Haozhe Du,Kenji Takahashi,Yusuke Mizukami,Kenzui Taniue, and Nobuyoshi Akimitsu
Genome Research Published:October 30, 2025
DOI:https://doi.org/10.1101/gr.280269.124

Abstract

RNA modifications play critical roles in cellular homeostasis and development by regulating gene expression, RNA metabolism, and translation. Their dysregulation contributes to the development of human diseases, including cancer. 3-methylcytidine (m³C) primarily occurs in transfer RNA, where it regulates translation, stem cell pluripotency, and mitochondrial function. m³C has also been detected in polyadenylated (poly[A]) RNA by mass spectrometric analysis; however, its transcriptome-wide distribution and functions remain unknown because of its low abundance and technical challenges. Here, we show that METTL2A, an m³C writer, is upregulated and associated with poor prognosis in pancreatic cancer tumors, while also being essential for pancreatic cancer cell proliferation. Using comparative nanopore direct RNA sequencing, we identify potential METTL2A-mediated m³C sites in poly(A) RNA. These m³C sites are mapped in both messenger RNA and mitochondrial RNA and are enriched in the CC motif and coding sequences. METTL2A knockdown alters expression of S100A4 mRNA isoforms, which contains METTL2A-mediated m³C sites. Notably, many transcripts with METTL2A-mediated m³C sites are upregulated upon METTL2A knockdown. We reveal the transcriptome-wide presence of m³C sites in poly(A) RNA and suggest their potential roles in regulating gene expression.