Transcription of a 5' extended mRNA isoform directs dynamic chromatin changes and interference of a downstream promoter
- The Francis Crick Institute, United Kingdom
- University of California, Berkeley, United States
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.
Article and author information
Author details
Folkert Jacobus van Werven
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.
Reviewing Editor
- Scott Keeney, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, United States
Version history
- Received: April 3, 2017
- Accepted: September 13, 2017
- Accepted Manuscript published: September 14, 2017 (version 1)
- Version of Record published: October 24, 2017 (version 2)
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.
Metrics
-
- 3,182
- views
-
- 522
- downloads
-
- 68
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- 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.
-
- Chromosomes and Gene Expression
Tardigrades are microscopic animals renowned for their ability to withstand extreme conditions, including high doses of ionizing radiation (IR). To better understand their radio-resistance, we first characterized induction and repair of DNA double- and single-strand breaks after exposure to IR in the model species Hypsibius exemplaris. Importantly, we found that the rate of single-strand breaks induced was roughly equivalent to that in human cells, suggesting that DNA repair plays a predominant role in tardigrades’ radio-resistance. To identify novel tardigrade-specific genes involved, we next conducted a comparative transcriptomics analysis across three different species. In all three species, many DNA repair genes were among the most strongly overexpressed genes alongside a novel tardigrade-specific gene, which we named Tardigrade DNA damage Response 1 (TDR1). We found that TDR1 protein interacts with DNA and forms aggregates at high concentration suggesting it may condensate DNA and preserve chromosome organization until DNA repair is accomplished. Remarkably, when expressed in human cells, TDR1 improved resistance to Bleomycin, a radiomimetic drug. Based on these findings, we propose that TDR1 is a novel tardigrade-specific gene conferring resistance to IR. Our study sheds light on mechanisms of DNA repair helping cope with high levels of DNA damage inflicted by IR.
