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Dissecting splicing decisions and cell-to-cell variability with designed sequence libraries

Author

Listed:
  • Martin Mikl

    (Weizmann Institute of Science
    Weizmann Institute of Science
    Weizmann Institute of Science)

  • Amit Hamburg

    (Weizmann Institute of Science
    Weizmann Institute of Science)

  • Yitzhak Pilpel

    (Weizmann Institute of Science)

  • Eran Segal

    (Weizmann Institute of Science
    Weizmann Institute of Science)

Abstract

Most human genes are alternatively spliced, allowing for a large expansion of the proteome. The multitude of regulatory inputs to splicing limits the potential to infer general principles from investigating native sequences. Here, we create a rationally designed library of >32,000 splicing events to dissect the complexity of splicing regulation through systematic sequence alterations. Measuring RNA and protein splice isoforms allows us to investigate both cause and effect of splicing decisions, quantify diverse regulatory inputs and accurately predict (R2 = 0.73–0.85) isoform ratios from sequence and secondary structure. By profiling individual cells, we measure the cell-to-cell variability of splicing decisions and show that it can be encoded in the DNA and influenced by regulatory inputs, opening the door for a novel, single-cell perspective on splicing regulation.

Suggested Citation

  • Martin Mikl & Amit Hamburg & Yitzhak Pilpel & Eran Segal, 2019. "Dissecting splicing decisions and cell-to-cell variability with designed sequence libraries," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12642-3
    DOI: 10.1038/s41467-019-12642-3
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    Cited by:

    1. Mariela Cortés-López & Laura Schulz & Mihaela Enculescu & Claudia Paret & Bea Spiekermann & Mathieu Quesnel-Vallières & Manuel Torres-Diz & Sebastian Unic & Anke Busch & Anna Orekhova & Monika Kuban &, 2022. "High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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