Sunday, October 7, 2007

Genome-wide recruitment of a transposon family for post-transcriptional gene regulation


A new paper just published in PLoS Pathogens is raising the bar on the potential for transposable elements to be co-opted for useful cellular functions. This remarkable story, which combines bioinformatics and biochemical experiments, provides several lines of evidence supporting an hypothesis put forward nearly 40 years ago by Roy Britten and Eric Davidson that interspersed repeats [derived from the propagation of TEs] can participate in the coordination of host gene expression and be harnessed to build regulatory networks.

Our story takes place in the trypanosomatid Leishmania major (pic on the right, courtesy of Dr Laurence Tetley). Trypanosomatids are single-celled, parasitic eukaryotes causing a variety of devastating diseases in humans, including leishmaniasis, sleeping sickness and Chagas disease. Recently, complete draft genome sequences of L. major and of two species of Trypanosoma were published. One of the most intriguing features of trypanosomatid genomes is that the bulk of their protein-coding genes are organized in large directional gene clusters (DGCs). Each DGC consists of multiple genes co-transcribed as a single pre-RNA molecule (also called a polycistron) that is processed post-transcriptionally into messenger RNAs prior to translation into different proteins. This organization is reminiscent of operons in bacteria. However, a distinct characteristic of trypanosome DGCs is that they do not appear to be regulated at the level of transcription. Indeed, they are no promoter elements identifiable upstream of trypanosomatid protein-coding genes and there seems no need to be. Indeed the RNA polymerase II (the transcription enzyme of) of trypanosomes is known to be unusual in that it can efficiently initiate transcription without any upstream promoter elements. Together, these observations (and others) indicate that trypanosomatid gene expression is almost exclusively regulated post-transcriptionally, which is at odds with what we know about gene regulation in most other organisms (see here for a good review). Gene regulation in trypanosomatids seems to occur predominantly at the levels of processing of the poly-cistronic transcripts and differential stability of the resulting mRNAs. Most of the regulatory sequences known to control stability of trypanosome mRNAs have been mapped to 3’ UTRs (untranslated regions), but the precise mechanism(s) by which the coordinated regulation of gene expression is achieved has remained elusive.

Using bioinformatics tools, Bringaud et al. discovered a family of retroposons in the Leishmania genome (i.e. short transposable elements that move via a RNA intermediate) called LmSIDER2. They found about 1,000 such elements dispersed in the L. major genome, which results from a relatively ancient genomic invasion. None of the elements appear to be able to transpose anymore and thus the entire TE family seems to be extinct. LmSIDER2 elements were found to have a strikingly biased distribution in the genome: they are almost exclusively located in the 3’ UTRs of predicted L. major mRNAs, suggesting a global role for these elements in post-transcriptional regulation. The authors go on to show experimentally that the presence of a SIDER copy in the 3’ UTR of a gene is not benign; it decreases the stability of the corresponding mRNA in vivo (the SIDER-containing mRNA has a shorter lifespan than one without SIDER). Consistent with these experiments, microarray analyses revealed that Leishmania mRNAs containing SIDER in their 3’ UTR are expressed generally at lower levels than non-SIDER containing mRNAs.

Together, these data suggest an intriguing scenario whereby SIDER elements have been recruited at a genome-wide scale to modulate the expression of hundreds of genes. The model offers a potential mechanism for coordinating gene expression at the post-transcriptional level and could be one strategy by which Leishmania has effectively ‘compensated’ for its loss of ability to control gene expression at the transcriptional level.

8 comments:

CAE said...

Cool stuff! Is it known whether the transposable element forms some kind of secondary RNA structure, or whether it binds to a protein that's involved in RNA stability?

One of the grad students in my old lab was working on something similar, but I was always more of a transcription geek.

BTW, have you considered submitting any of your articles to a blog carnival? I found it to be a great way of getting a new blog off the ground. It just so happens (heh) that I'm hosting the next edition of Mendel's Garden, a genetics blog as you might expect... check it out here!

CedricF said...

The mechanism by which the SIDER elements destabilize mRNA is not known. In this study, they simply show that the presence of the element is associated with shorter lifespan of the mRNA. They didn't speculate further on the possible mechanism.

As for the blog carnival, this is not something I was familiar with. These bloggers have created their own little world and the language that comes with it! Definitely I will try to post something on November's edition of Mendel's Garden. But do I really want this blog to get 'off the ground', if I cannot even keep it on the ground?! Underground might really be the best spot for me ;)

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