SAGA: an underestimated role in the transcription of our genes
While the amount of total mRNA seemed little affected when SAGA is inhibited (bottom), the net production of new mRNA in the mutants is drastically reduced on all the genes (top).
Sept. 15, 2014
A study coordinated by Didier Devys in Làszlò Tora’s team at the IGBMC highlights the crucial role of the SAGA coactivator complex in the transcription of our genes, largely underestimated so far. Indeed they proved that it has a role throughout the entire transcribed genome and is essential for proper functioning of the RNA polymerase II. These results are published on September 15th in the journal Genes & Development.
In addition to the RNA polymerase II which catalyzes transcription, the expression of genes encoding proteins requires the action of many molecules: the general transcription factors act in concert with this enzyme, while the activators bind upstream DNA sequences and work with coactivators that bind to them in order to "open" chromatin and facilitate the access of the transcriptional machinery to the promoter DNA sequence. It is generally accepted that each coactivator is associated with a specific group of genes.
Here the researchers got interested in the SAGA coactivator whose action seemed limited to the transcription of certain genes. This coactivator is responsible for two important chromatin modifications: acetylation of histone H3K9 and deubiquitination of histone H2B. Instead of trying to observe the binding sites of SAGA on DNA, which is difficult as it does not bind directly but via an activator, the researchers directly located these modifications on the genome. To their surprise, they showed that SAGA acts on all expressed genes, the H3K9 acetylation occurring at the promoter of genes, and the H2B deubiquitination on the transcribed sequence. According to Didier Devys, "The SAGA complex can affect the entire genome in less than 10 minutes. This extremely fast dynamics coupled with a technique that produces averages on a heterogeneous population (Chip-seq) likely explains why previous studies showed only part of SAGA sites of action".
The researchers then went further to assess the role of SAGA in transcription. By inactivating the complex, they first observed a significant decrease in the recruitment of RNA polymerase II on all active genes. They then evaluated the role of SAGA on production of messenger RNA. Once more, while their colleagues’ results showed little impact of the absence of SAGA on the amount of mRNA in the cell, Didier’s team got interested in the production of new mRNA and not in the net amount present in the cell. The results of this analysis have proved clear: The absence of SAGA has a drastic effect on gene transcription and mRNA production. "The amount of mRNA in the cell is finely controlled and dependent on its production but also its degradation. If an overall decrease in mRNA production occurs, the cell is able to adapt and to limit its degradation mechanisms. Measuring the overall amount of mRNA in the cell does not allow to assess changes in DNA transcription" says Didier Devys.
These results illustrate how the investigation field of gene expression and biology is broad and difficult to decrypt. The biological mechanisms are intertwined and involve a multitude of molecules, which complicates the interpretation of analyzes. In the end, in this study the researchers managed to restore the importance of a protein complex whose role was largely underestimated.