RNA生成の初期段階を可視化する新手法を開発(Yale-developed method offers view into earliest stages of RNA production)

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2025-05-05 イェール大学

イェール大学の研究チームは、RNA分子が合成される最初期の構造を可視化する新手法「CoSTseq(共転写構造追跡)」を開発しました。この技術は、RNA合成中に特定の時点で分子を分離し、化学修飾を加えることで、RNAが成長する過程での構造変化を追跡します。従来は成熟したRNA構造のみが解析対象でしたが、CoSTseqにより、RNAの初期折りたたみ構造が明らかとなり、これらが遺伝子発現や疾患に与える影響の解明が期待されます。研究は、イェール大学分子生物物理学・生化学部門の博士課程学生レナード・シャーフェン氏が主導し、カール・ノイゲバウアー教授がシニア著者として参加しました。この成果は、RNAの構造形成過程を理解し、将来的な治療法の開発に貢献する可能性があります。

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新生RNAの迅速なフォールディングが真核生物のRNA生合成を制御する Rapid folding of nascent RNA regulates eukaryotic RNA biogenesis

Leonard Schärfen ∙ Isaac W. Vock ∙ Matthew D. Simon ∙ Karla M. Neugebauer
Molecular Cell  Published:March 25, 2025
DOI:https://doi.org/10.1016/j.molcel.2025.02.025

Graphical abstract

RNA生成の初期段階を可視化する新手法を開発(Yale-developed method offers view into earliest stages of RNA production)

Highlights

  • CoSTseq detects nascent RNA base pairing upon exit from RNA polymerases in vivo
  • Base pairing occurs rapidly within 25 bp of transcription after addition to the RNA
  • Nascent rRNA structure is vastly different from mature rRNA
  • Cytoplasmic mRNA structure is largely indistinguishable from nascent pre-mRNA

Summary

RNA’s catalytic, regulatory, or coding potential depends on structure formation. Because base pairing occurs during transcription, early structural states can govern RNA processing events and dictate the formation of functional conformations. These co-transcriptional states remain mostly unknown. Here, we develop co-transcriptional structure tracking (CoSTseq), which detects nascent RNA base pairing within and upon exit from RNA polymerases (Pols) transcriptome wide in living yeast cells. Monitoring each nucleotide’s base pairing activity during transcription, CoSTseq reveals predominantly rapid pairing—within 25 bp of transcription after addition to the nascent chain. Moreover, ∼23% of rRNA nucleotides attain their final base pairing state near Pol I, while most other nucleotides must undergo changes in pairing status during later steps of ribosome biogenesis. We show that helicases act immediately to remodel structures across the rDNA locus to facilitate ribosome biogenesis. By contrast, nascent pre-mRNAs attain local structures indistinguishable from mature mRNAs, suggesting that refolding behind elongating ribosomes resembles co-transcriptional folding behind Pol II.

生物工学一般
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