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

Martin Mikl, Amit Hamburg, Yitzhak Pilpel, Eran Segal

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number4572
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology

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