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David Baulcombe Discusses microRNAs in Single-Cell Organisms

Name: David Baulcombe
Position: Senior research scientist, Sainsbury Laboratory, John Innes Centre
Background: Principal scientific officer, Plant Breeding Institute — 1980-1988
Postdoc, University of Georgia, Athens — 1978-1980
Postdoc, McGill University — 1977-1978
PhD, botany, University of Edinburgh — 1977
BSc, botany, University of Leeds — 1973

In this week’s Nature, David Baulcombe and colleagues from the Sainsbury Laboratory at the John Innes Centre published data showing that microRNAs are present and active in the green algae Chlamydomonas reinhardtii.
“Until now, miRNAs have not been described in unicellular organisms, and it has been suggested that they evolved together with multicellularity in separate plant and animal lineages,” the paper’s authors wrote. “We show that the unicellular alga Chlamydomonas reinhardtii contains miRNAs, putative evolutionary precursors of miRNAs, and a species of siRNAs resembling those in higher plants.
“The common features of miRNAs and siRNAs in an alga and in higher plants indicate that complex RNA-silencing systems evolved before multicellularity and were a feature of primitive eukaryotic cells,” they added.
This week, RNAi News interviewed Baulcombe via e-mail and telephone to discuss the findings, as well as how the first meeting of the recently launched “Silencing RNAs: Organizers and Coordinators of Complexity in Eukaryotic Organisms” consortium went.
Can you give an overview of the experiments you conducted to find microRNAs in Chlamydomonas?
For the story to make sense your readers would need to understand that there is a growing family of short silencing RNAs known from different organisms — there are various types of short interfering RNAs [including] transposon, repeat associated, transacting [factors], natural antisense and others, [as well as] microRNAs. They differ depending on the biogenesis mechanism, type of precursor RNA, [and] targeting mechanism, [that is] transcriptional versus post-transcriptional or translational. …
[As far as conducting the research, we first used] high-throughput sequencing to get the sequence of tens of thousands of short RNAs. Second, [we examined] alignment of the sequence to the genome sequence so that the short RNA genes could be identified.
Computational analyses [were then conducted] to identify small RNA genes with the characteristics of miRNA genes, i.e. the precursor RNA would fold back on itself to form a molecule with a base paired domain and there would just be a single short RNA derived from that domain. The fourth step [was] then identification of the likely mRNA target of the miRNA and [then] … experimental validation that these RNAs are targeted. …
I suppose … the surprising finding [from the Nature paper] is that this green alga has such a complex set of short silencing RNAs including transposon, [microRNAs], and some that look like transacting [factors]. We might have expected that it would have transposon siRNAs — transposon silencing for genome defense might have been a function of RNAi in a primitive eukaryotic precursor of plants and animals. But the others would not have been expected, especially microRNAs.
The previous view of microRNAs is that they probably evolved independently in plant and animal lineages associated with the acquisition of complex regulatory mechanisms associated with multicellularity. Clearly that is not the case, and the implication is that RNA silencing systems might have roles related to basic cell function — for example, in conferring robustness on RNA-based regulatory networks
So when you began the work, you didn’t expect that you might find microRNAs?
I don’t think we expected to find them. We set up the analysis for the purpose of characterizing the small RNAs in [C. reinhardtii] because we wanted a different experimental system other than the higher plants that we do most of our work with. Also, we thought from an evolutionary point of view that it would be interesting to find out what an alga had, [which] could be informative about what a common ancestor of algae and higher plants had.
We had an open mind, but if you’d asked me to put money on it before we actually did the experiments, I would have said that we would not have expected to find microRNAs.
Why did you choose Chlamydomonas for these experiments?
First, little is known about silencing RNAs in [unicellular organisms]. Second, it is a green yeast and highly suitable for analysis of basic processes including cell division, gametogenesis, meiosis. Consequently, in later stages of the work, it will be possible to investigate the effect of silencing on these basic mechanisms.
[Also], the [Chlamydomonas] genome sequence has recently been completed and so it is now easy to make sense of the small RNA sequence data.
Isn’t a form of RNA-gene regulation mechanism already known to exist in certain unicellular organisms such as yeast and bacteria?
RNA silencing is really a eukaryotic process. Fission yeast has something similar that mediates silencing of chromatin rather than RNA degradation as with microRNAs. Other [unicellular organisms] may also have RNA silencing-based mechanisms that silence transposons or that are involved in macronuclear differentiation in tetrahymena and paramecium, but until now miRNAs were known only from [multicellular organisms].
I guess it is not yet clear why some regulatory mechanisms should be based on miRNAs — they are often associated with feedback mechanisms and in Drosophila they have been implicated in robustness of regulatory states rather than on off switching. So that is what we will be looking for in [Chlamydomonas].
In the May 15 issue of Genes & Development, researchers from the National Institute of Biological Sciences in China, the ChineseAcademy of Sciences, and ColdSpringHarbor Laboratory published a report showing the presence of microRNAs in C. reinhardtii. How similar are the findings between the two papers?
There is a substantial overlap between the papers, [but] it is always useful to have confirmation.
Shifting gears a bit, SIROCCO, [an EU-funded consortium of RNAi and miRNA researchers], recently had its first meeting (see RNAi News, 4/26/2007). How did that go?
It was very good. It was really just a getting-to-know-you meeting. As you know, the whole consortium involves people working with a wide range of systems — not everybody knew each other before. The impression we got was that there is a very good prospect, despite the diversity of systems, for everybody working together and making the whole more than the sum of its parts.
When is the next meeting planned?
The next meeting will be some time in November.
Will that meeting be more driven by research and data found since the first?
This will be when our first annual report is due, so it will be partly an update on the progress of the research … allowing us to see what the highlights are for the reporting period. [It will also allow us to get] a view as to how we plan the research program going forward.

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