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Splicing activates transcription from weak promoters upstream of alternative exons

Author

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  • Maritere Uriostegui-Arcos

    (Boston University)

  • Steven T. Mick

    (Boston University)

  • Zhuo Shi

    (Massachusetts Institute of Technology)

  • Rufuto Rahman

    (Boston University)

  • Ana Fiszbein

    (Boston University)

Abstract

Transcription and splicing are intrinsically coupled. Alternative splicing of internal exons can fine-tune gene expression through a recently described phenomenon called exon-mediated activation of transcription starts (EMATS). However, the association of this phenomenon with human diseases remains unknown. Here, we develop a strategy to activate gene expression through EMATS and demonstrate its potential for treatment of genetic diseases caused by loss of expression of essential genes. We first identified a catalog of human EMATS genes and provide a list of their pathological variants. To test if EMATS can be used to activate gene expression, we constructed stable cell lines expressing a splicing reporter based on the alternative splicing of motor neuron 2 (SMN2) gene. Using small molecules and antisense oligonucleotides (ASOs) currently used for treatment of spinal muscular atrophy, we demonstrated that increase of inclusion of alternative exons can trigger an activation of gene expression up to 45-fold by enhancing transcription in EMATS-like genes. We observed the strongest effects in genes under the regulation of weak human promoters located proximal to highly included skipped exons.

Suggested Citation

  • Maritere Uriostegui-Arcos & Steven T. Mick & Zhuo Shi & Rufuto Rahman & Ana Fiszbein, 2023. "Splicing activates transcription from weak promoters upstream of alternative exons," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39200-2
    DOI: 10.1038/s41467-023-39200-2
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    References listed on IDEAS

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    1. Michael Lawrence & Wolfgang Huber & Hervé Pagès & Patrick Aboyoun & Marc Carlson & Robert Gentleman & Martin T Morgan & Vincent J Carey, 2013. "Software for Computing and Annotating Genomic Ranges," PLOS Computational Biology, Public Library of Science, vol. 9(8), pages 1-10, August.
    2. Joel M. Gottesfeld & Laura Neely & John W. Trauger & Eldon E. Baird & Peter B. Dervan, 1997. "Regulation of gene expression by small molecules," Nature, Nature, vol. 387(6629), pages 202-205, May.
    3. Kian Huat Lim & Zhou Han & Hyun Yong Jeon & Jacob Kach & Enxuan Jing & Sebastien Weyn-Vanhentenryck & Mikaela Downs & Anna Corrionero & Raymond Oh & Juergen Scharner & Aditya Venkatesh & Sophina Ji & , 2020. "Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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