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Molecular Biology

Nuclear Architecture and Gene Expression

New and exciting things are happening in the field of gene expression: Two research teams have demonstrated the importance of spatial organization in the regulation of gene expression.

pasteur

© J. C.Olivo-Marin/CNRS-Institut Pasteur

Ulf Nehrbass and his team tracked a gene's movement after activation: They observed that it settled in the nucleus' periphery (a requirement for gene expression) and that its mobility was reduced.


 

In eukaryotic cells, the genome is compacted into nucleoprotein filaments–chromatin– consisting of a mixture of DNA and proteins. Chromatin is organized in three dimensions within the nucleus, which is separated from the rest of the cell by the nuclear envelope.

Angela Taddei,1 on Susan Gasser's team, has studied the HXK1 gene of budding yeast.2 The expression of this gene is activated in two different ways: either by growth in the absence of glucose, or by stimulation by a molecular factor called VP16. In both cases, the gene is activated and expressed. However, its level of expression and its location within the nucleus differ. Taddei and coworkers show that when yeast cells are grown in the absence of glucose, the HXK1 gene associates with pores in the nuclear envelope and is strongly expressed. By contrast, if the gene is activated by the VP16 pathway, it is found further away from the periphery of the nucleus, and is expressed less strongly.

Next, researchers wanted to see which of the two pathways would “win.” Therefore, yeast cells were grown in the absence of glucose but in the presence of VP16, so that both activation pathways were triggered. The VP16 pathway proved to be the stronger: The gene moved away from the periphery and its expression decreased as compared to the glucose-free medium activation. According to Taddei, “This suggests that it is vital for the gene to be attached to the envelope for maximal expression.” To test this hypothesis, they artificially associated the gene with the periphery of the nucleus: Its activation on glucose-free medium was increased. Furthermore, elimination of the 3'-untranslated region of the gene (a small region downstream from the gene  responsible for exporting mRNA out of the nucleus) resulted in a weaker association with the nuclear envelope and weaker expression. These findings concur with those obtained by the team led by Ulf Nehrbass of the Pasteur Institute.3 The work of these two teams was published back-to-back in Nature, in June 2006.4

With great technical prowess, the Pasteur Institute biologists were able to follow in real time the movement of genes during their activation. “This technological advance is remarkable in itself,” claims Nehrbass. “It's the first time that we have been able to follow in real time the movement of a gene, in three dimensions, inside the nucleus.” This group also studied budding yeast cells, but used the GAL gene. Their first finding was that gene movements decrease during activation. Results obtained by Nehrbass's team suggest that transcription factors, already known to be involved in gene expression, seem to have an additional role: immobilizing the active gene in a particular configuration. “When the gene is activated, it seems to slide along the nuclear envelope,” explains Nehrbass. The attachment of the gene to the envelope is therefore dynamic. For him, the most important finding of this research is the contribution of spatial organization to the regulation of gene expression. “Cells make use of architecture to code epigenetic information. The DNA sequence alone doesn't determine everything,” he insists. “Our entire understanding of gene expression will have to be revised in light of this new concept.” Nehrbass, currently working in Korea, highlights how these discoveries could be medically important. “The nuclear envelope of cancer cells is often deformed. We used to believe that it was a consequence of the disease, whereas it now seems more likely to be a cause,” he explains. Identifying a new cause of disease is the first step toward finding a new target for treatments. There is no doubt that this work has opened entirely new avenues of research for cancer treatment.

 

Julie Coquart

Notes :

1. Nuclear Dynamics and Genome Plasticity Laboratory (CNRS / Institut Curie joint lab). Taddei is currently working at the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.
2. A. Taddei et al., “Nuclear pore association confers optimal expression levels for an inducible yeast gene,” Nature. 441 (7094): 774-8. 2006.
3. Nuclear Cell Biology Unit (CNRS / Pasteur Institute joint lab).
4. G. G. Cabal et al., “SAGA interacting factors confine sub-diffusion of transcribed genes to the nuclear envelope,” Nature. 441 (7094): 770-3. 2006.

Contacts :

> Angela Taddei
angela.taddei@fmi.ch
> Ulf Nehrbass
nehrbass@pasteur.or.kr


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