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Antagonistic controls of chromatin and mRNA start site selection by Tup family corepressors and the CCAAT-binding
Ryuta Asada1, Naomichi Takemata2, Charles S Hoffman3
1Department of Chemistry, Graduate School of Science and Engineering, Tokyo Metropolitan University, Tokyo, Japan.
Abstract:
The Tup family corepressors contribute to critical cellular responses, such as the stress response and differentiation, presumably by inducing repressive chromatin, though the precise repression mechanism remains to be elucidated. The Schizosaccharomyces pombe fission yeast Tup family corepressors Tup11 and Tup12 (Tup11/12), which are orthologs of Tup1 in Saccharomyces cerevisiae budding yeast and Groucho in Drosophila, negatively control chromatin and the transcriptional activity of some stress-responsive genes. Here, we demonstrate that Tup11/12 repress transcription of a gluconeogenesis gene, fbp1⁺, by three distinct mechanisms. First, Tup11/12 inhibit chromatin remodeling in the fbp1⁺ promoter region where the Atf1 and Rst2 transcriptional activators bind. Second, they repress the formation of an open chromatin configuration at the fbp1⁺ TATA box. Third, they repress mRNA transcription per se by regulating basic transcription factors. These inhibitory actions of Tup11/12 are antagonized by three different types of transcriptional activators: CREB/ATF-type Atf1, C₂H₂zinc finger-type Rst2, and CBF/NF-Y-type Php5 proteins. We also found that impaired chromatin remodeling and fbp1⁺ mRNA transcription in php5Δ strains are rescued by the double deletions of tup11⁺ and tup12⁺, although the distribution of the transcription start sites becomes broader than that in wild-type cells. These data reveal a new mechanism of precise determination of the mRNA start site by Tup family corepressors and CBF/NF-Y proteins.
Insights
The fission yeast Tup11/12 corepressors use three mechanisms to repress gluconeogenesis gene transcription. These include inhibiting chromatin remodeling, TATA box accessibility, and basic transcription factor regulation.
Area of Science:
- Molecular Biology
- Epigenetics
- Yeast Genetics
Background:
- Tup family corepressors regulate cellular responses like stress and differentiation through chromatin.
- Schizosaccharomyces pombe Tup11/12 are orthologs of yeast Tup1 and Drosophila Groucho.
- The precise repression mechanisms of Tup family corepressors remain largely unknown.
Purpose of the Study:
- To elucidate the repression mechanisms of Tup11/12 on the gluconeogenesis gene fbp1⁺ in fission yeast.
- To identify transcriptional activators that antagonize Tup11/12-mediated repression.
- To investigate the role of Tup11/12 and activators in determining transcription start site precision.
Main Methods:
- Analysis of Tup11/12 (Tup11 and Tup12) function in Schizosaccharomyces pombe.
- Chromatin remodeling assays at the fbp1⁺ promoter and TATA box.
- Investigation of mRNA transcription and transcription start site distribution in wild-type and mutant strains (e.g., php5Δ, tup11Δ tup12Δ).
Main Results:
- Tup11/12 repress fbp1⁺ transcription via three distinct mechanisms: inhibiting chromatin remodeling, blocking TATA box accessibility, and regulating basic transcription factors.
- Transcriptional activators Atf1, Rst2, and Php5 antagonize Tup11/12 repression.
- Deletion of tup11⁺/tup12⁺ rescues chromatin remodeling and transcription defects in php5Δ strains, albeit with broader transcription start site distribution.
Conclusions:
- Tup11/12 employ multiple mechanisms to achieve precise transcriptional repression of the fbp1⁺ gene.
- Tup family corepressors and CBF/NF-Y proteins (like Php5) collaborate to determine accurate mRNA start sites.
- This study reveals a novel mechanism for precise mRNA start site determination involving corepressors and specific activators.
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