Kinetochore inactivation by expression of a repressive mRNA
- University of California, Berkeley, United States
- The Francis Crick Institute, United Kingdom
- Li Ka Shing Center, University of California, United States
- University of California, United States
Abstract
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.
Data availability
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High-resolution view of the yeast meiotic program revealed by ribosome profilingPublicly available at the NCBI Gene Expression Omnibus (accession no. GSE34082).
Article and author information
Author details
Folkert Jacobus van Werven
Funding
March of Dimes Foundation (5-FY15-99)
- Elcin Unal
Pew Charitable Trusts (27344)
- Elcin Unal
Glenn Foundation for Medical Research
- Elcin Unal
Francis Crick Institute
- Folkert Jacobus van Werven
National Science Foundation
- Jingxun Chen
Agency for Science, Technology and Research
- Minghao Chia
Damon Runyon Cancer Research Foundation (35-15)
- Elcin Unal
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Scott Keeney, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, United States
Version history
- Received: April 3, 2017
- Accepted: September 1, 2017
- Accepted Manuscript published: September 14, 2017 (version 1)
- Version of Record published: October 24, 2017 (version 2)
Copyright
© 2017, Chen 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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Kinetochore inactivation by expression of a repressive mRNA
eLife 6:e27417.
https://doi.org/10.7554/eLife.27417
Further reading
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- Chromosomes and Gene Expression
A key protein involved in the segregation of meiotic chromosomes is produced 'just in time' by the regulated expression of two mRNA isoforms.
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- Chromosomes and Gene Expression
- Developmental Biology
Developmental programming involves the accurate conversion of signalling levels and dynamics to transcriptional outputs. The transcriptional relay in the Notch pathway relies on nuclear complexes containing the co-activator Mastermind (Mam). By tracking these complexes in real time, we reveal that they promote the formation of a dynamic transcription hub in Notch ON nuclei which concentrates key factors including the Mediator CDK module. The composition of the hub is labile and persists after Notch withdrawal conferring a memory that enables rapid reformation. Surprisingly, only a third of Notch ON hubs progress to a state with nascent transcription, which correlates with polymerase II and core Mediator recruitment. This probability is increased by a second signal. The discovery that target-gene transcription is probabilistic has far-reaching implications because it implies that stochastic differences in Notch pathway output can arise downstream of receptor activation.
