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Transcriptional stochasticity reveals multiple mechanisms of long non-coding RNA regulation at the Xist–Tsix locus

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  • Benjamin K. Kesler

    (Vanderbilt University)

  • John Adams

    (Vanderbilt University)

  • Gregor Neuert

    (Vanderbilt University
    Vanderbilt University
    Vanderbilt University
    Vanderbilt University)

Abstract

Long noncoding RNAs (LncRNAs) are increasingly recognized as being involved in human physiology and diseases, but there is a lack of mechanistic understanding for the majority of lncRNAs. We comparatively test proposed mechanisms of antisense lncRNA regulation at the X-chromosome Inactivation (XCI) locus. We find that due to stochasticity in transcription, different mechanisms based on the act of transcription regulate Xist and Tsix at different levels of nascent transcription. At medium levels, RNA polymerases transcribe Xist and Tsix on each strand at the same transcription site and deposit significant amounts of the histone mark H3K36me3, which inhibits Xist. At high levels of nascent transcription, many RNA polymerases transcribe Xist or Tsix resulting in transcriptional interference. Therefore, lncRNA expression variability is not just a quirk of transcription but an important aspect of regulation that allows multiple mechanisms to be employed by the same gene locus within the same cell population.

Suggested Citation

  • Benjamin K. Kesler & John Adams & Gregor Neuert, 2025. "Transcriptional stochasticity reveals multiple mechanisms of long non-coding RNA regulation at the Xist–Tsix locus," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59496-6
    DOI: 10.1038/s41467-025-59496-6
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    References listed on IDEAS

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    1. Mrinal K. Sarkar & Srimonta Gayen & Surinder Kumar & Emily Maclary & Emily Buttigieg & Michael Hinten & Archana Kumari & Clair Harris & Takashi Sado & Sundeep Kalantry, 2015. "An Xist-activating antisense RNA required for X-chromosome inactivation," Nature Communications, Nature, vol. 6(1), pages 1-13, December.
    2. Mélanie Makhlouf & Jean-François Ouimette & Andrew Oldfield & Pablo Navarro & Damien Neuillet & Claire Rougeulle, 2014. "A prominent and conserved role for YY1 in Xist transcriptional activation," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
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