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Buffering of transcription rate by mRNA half-life is a conserved feature of Rett syndrome models

Author

Listed:
  • Deivid C. Rodrigues

    (Hospital for Sick Children)

  • Marat Mufteev

    (Hospital for Sick Children
    University of Toronto)

  • Kyoko E. Yuki

    (Hospital for Sick Children)

  • Ashrut Narula

    (University of Toronto
    Hospital for Sick Children)

  • Wei Wei

    (Hospital for Sick Children)

  • Alina Piekna

    (Hospital for Sick Children)

  • Jiajie Liu

    (Hospital for Sick Children)

  • Peter Pasceri

    (Hospital for Sick Children)

  • Olivia S. Rissland

    (Hospital for Sick Children
    University of Colorado School of Medicine)

  • Michael D. Wilson

    (University of Toronto
    Hospital for Sick Children)

  • James Ellis

    (Hospital for Sick Children
    University of Toronto)

Abstract

Transcriptional changes in Rett syndrome (RTT) are assumed to directly correlate with steady-state mRNA levels, but limited evidence in mice suggests that changes in transcription can be compensated by post-transcriptional regulation. We measure transcription rate and mRNA half-life changes in RTT patient neurons using RATEseq, and re-interpret nuclear and whole-cell RNAseq from Mecp2 mice. Genes are dysregulated by changing transcription rate or half-life and are buffered when both change. We utilized classifier models to predict the direction of transcription rate changes and find that combined frequencies of three dinucleotides are better predictors than CA and CG. MicroRNA and RNA-binding Protein (RBP) motifs are enriched in 3ʹUTRs of genes with half-life changes. Nuclear RBP motifs are enriched on buffered genes with increased transcription rate. We identify post-transcriptional mechanisms in humans and mice that alter half-life or buffer transcription rate changes when a transcriptional modulator gene is mutated in a neurodevelopmental disorder.

Suggested Citation

  • Deivid C. Rodrigues & Marat Mufteev & Kyoko E. Yuki & Ashrut Narula & Wei Wei & Alina Piekna & Jiajie Liu & Peter Pasceri & Olivia S. Rissland & Michael D. Wilson & James Ellis, 2023. "Buffering of transcription rate by mRNA half-life is a conserved feature of Rett syndrome models," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37339-6
    DOI: 10.1038/s41467-023-37339-6
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    References listed on IDEAS

    as
    1. Debashish Ray & Hilal Kazan & Kate B. Cook & Matthew T. Weirauch & Hamed S. Najafabadi & Xiao Li & Serge Gueroussov & Mihai Albu & Hong Zheng & Ally Yang & Hong Na & Manuel Irimia & Leah H. Matzat & R, 2013. "A compendium of RNA-binding motifs for decoding gene regulation," Nature, Nature, vol. 499(7457), pages 172-177, July.
    2. Harrison W. Gabel & Benyam Kinde & Hume Stroud & Caitlin S. Gilbert & David A. Harmin & Nathaniel R. Kastan & Martin Hemberg & Daniel H. Ebert & Michael E. Greenberg, 2015. "Disruption of DNA-methylation-dependent long gene repression in Rett syndrome," Nature, Nature, vol. 522(7554), pages 89-93, June.
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