1. Chromosomes and Gene Expression

Transcription of a 5' extended mRNA isoform directs dynamic chromatin changes and interference of a downstream promoter

  1. Minghao Chia
  2. Amy Tresenrider
  3. Jingxun Chen
  4. Gianpiero Spedale
  5. Victoria Jorgensen
  6. Elçin Ünal  Is a corresponding author
  7. Folkert Jacobus van Werven  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. University of California, Berkeley, United States
https://doi.org/10.7554/eLife.27420
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Cite this article
  1. Minghao Chia
  2. Amy Tresenrider
  3. Jingxun Chen
  4. Gianpiero Spedale
  5. Victoria Jorgensen
  6. Elçin Ünal
  7. Folkert Jacobus van Werven
(2017)
Transcription of a 5' extended mRNA isoform directs dynamic chromatin changes and interference of a downstream promoter
eLife 6:e27420.
https://doi.org/10.7554/eLife.27420
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Abstract

Cell differentiation programs require dynamic regulation of gene expression. During meiotic prophase in Saccharomyces cerevisiae, expression of the kinetochore complex subunit Ndc80 is downregulated by a 5' extended long undecoded NDC80 transcript isoform. Here we demonstrate a transcriptional interference mechanism that is responsible for inhibiting expression of the coding NDC80 mRNA isoform. Transcription from a distal NDC80 promoter directs Set1-dependent histone H3K4 dimethylation and Set2-dependent H3K36 trimethylation to establish a repressive chromatin state in the downstream canonical NDC80 promoter. As a consequence, NDC80 expression is repressed during meiotic prophase. The transcriptional mechanism described here is rapidly reversible, adaptable to fine-tune gene expression, and relies on Set2 and the Set3 histone deacetylase complex. Thus, expression of a 5' extended mRNA isoform causes transcriptional interference at the downstream promoter. We demonstrate that this is an effective mechanism to promote dynamic changes in gene expression during cell differentiation.

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Author details

  1. Minghao Chia

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Amy Tresenrider

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Jingxun Chen

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Gianpiero Spedale

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Victoria Jorgensen

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Elçin Ünal

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    elcin@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.

  7. Folkert Jacobus van Werven

    The Francis Crick Institute, London, United Kingdom
    For correspondence
    folkert.vanwerven@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6685-2084

Funding

Francis Crick Institute (FC001203)

  • Folkert Jacobus van Werven

Pew Charitable Trusts (27344)

  • Elçin Ünal

Glenn Foundation for Medical Research

  • Elçin Ünal

March of Dimes Foundation (5-FY15-99)

  • Elçin Ünal

National Science Foundation (DGE-1106400 Graduate Student Fellowship)

  • Jingxun Chen
  • Elçin Ünal

Agency for Science, Technology and Research (Graduate Student Fellowship)

  • Minghao Chia

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2017, Chia et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Minghao Chia
  2. Amy Tresenrider
  3. Jingxun Chen
  4. Gianpiero Spedale
  5. Victoria Jorgensen
  6. Elçin Ünal
  7. Folkert Jacobus van Werven
(2017)
Transcription of a 5' extended mRNA isoform directs dynamic chromatin changes and interference of a downstream promoter
eLife 6:e27420.
https://doi.org/10.7554/eLife.27420

Share this article

https://doi.org/10.7554/eLife.27420

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Further reading

    1. Chromosomes and Gene Expression

    Kinetochore inactivation by expression of a repressive mRNA

    Jingxun Chen, Amy Tresenrider ... Elçin Ünal
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    Differentiation programs such as meiosis depend on extensive gene regulation to mediate cellular morphogenesis. Meiosis requires transient removal of the outer kinetochore, the complex that connects microtubules to chromosomes. How the meiotic gene expression program temporally restricts kinetochore function is unknown. We discovered that in budding yeast, kinetochore inactivation occurs by reducing the abundance of a limiting subunit, Ndc80. Furthermore, we uncovered an integrated mechanism that acts at the transcriptional and translational level to repress NDC80 expression. Central to this mechanism is the developmentally controlled transcription of an alternate NDC80 mRNA isoform, which itself cannot produce protein due to regulatory upstream ORFs in its extended 5’ leader. Instead, transcription of this isoform represses the canonical NDC80 mRNA expression in cis, thereby inhibiting Ndc80 protein synthesis. This model of gene regulation raises the intriguing notion that transcription of an mRNA, despite carrying a canonical coding sequence, can directly cause gene repression.

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