効率的なmRNAスプライシングのために遺伝子が空間的に組織化される(Genes Spatially Organize for Efficient mRNA Splicing)

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2024-05-08 カリフォルニア工科大学(Caltech)

カリフォルニア工科大学のミッチ・ガットマン教授の研究チームは、細胞核に存在する「核斑点」と呼ばれる核小体が、mRNAの効率的な生産を可能にする小さな工場のように機能することを発見しました。この核斑点はスプライシング酵素が高濃度に含まれており、遺伝子はこれに近接するように配置されることで、mRNAへの転写とスプライシングが効率的に行われます。この発見は、細胞機能と核の構造の関係を理解する上での基礎科学だけでなく、mRNAスプライシングが関与する疾患、特にALSのような神経変性疾患の治療薬開発にも影響を与える可能性があります。

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核斑点を中心としたゲノムの組織化がmRNAのスプライシング効率を高める Genome organization around nuclear speckles drives mRNA splicing efficiency

Prashant Bhat,Amy Chow,Benjamin Emert,Olivia Ettlin,Sofia A. Quinodoz,Mackenzie Strehle,Yodai Takei,Alex Burr,Isabel N. Goronzy,Allen W. Chen,Wesley Huang,Jose Lorenzo M. Ferrer,Elizabeth Soehalim,Say-Tar Goh,Tara Chari,Delaney K. Sullivan,Mario R. Blanco & Mitchell Guttman
Nature  Published:08 May 2024
DOI:https://doi.org/10.1038/s41586-024-07429-6

効率的なmRNAスプライシングのために遺伝子が空間的に組織化される(Genes Spatially Organize for Efficient mRNA Splicing)

Abstract

The nucleus is highly organized, such that factors involved in the transcription and processing of distinct classes of RNA are confined within specific nuclear bodies. One example is the nuclear speckle, which is defined by high concentrations of protein and noncoding RNA regulators of pre-mRNA splicing. What functional role, if any, speckles might play in the process of mRNA splicing is unclear. Here we show that genes localized near nuclear speckles display higher spliceosome concentrations, increased spliceosome binding to their pre-mRNAs and higher co-transcriptional splicing levels than genes that are located farther from nuclear speckles. Gene organization around nuclear speckles is dynamic between cell types, and changes in speckle proximity lead to differences in splicing efficiency. Finally, directed recruitment of a pre-mRNA to nuclear speckles is sufficient to increase mRNA splicing levels. Together, our results integrate the long-standing observations of nuclear speckles with the biochemistry of mRNA splicing and demonstrate a crucial role for dynamic three-dimensional spatial organization of genomic DNA in driving spliceosome concentrations and controlling the efficiency of mRNA splicing.

細胞遺伝子工学
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