Wednesday, 16 July 2008

Yet another twist in the world of gene expression - transcription factories

ResearchBlogging.orgWhen I went to a conference on post translational modification and chromatin, one talk really grabbed me, ironically it was the one that didn’t relate to the topic of the conference. I was going to facebook people about it and then remembered this existed.

First of all I will ask you, did you know that transcription only happened at a few sites within the nucleus? In mouse cells from the animal there are between 100-300 of these but in cultured cells such as HeLa cells there are many more. Transcription factories also known as RNAPII foci are where most, if not all mRNA is produced. This amazed me and raises the obvious questions of why and how. The why may be obvious. It is a good idea to keep the nucleus as I see it ‘tidy’ but in more technical terms it is a way of keeps gene expression organised and regulating it (see below). The how this work I don’t think has been addressed! All I can say is watch this space.

Another interesting feature of mammalian gene expression that has come out of these studies is that most ‘active genes’ are not on all the time like classically thought. Most genes appear to show a pulse fashion of expression. Travelling to transcription factories and being expressed then returning to a dormant stage until they travel back to transcription foci for another round of expression and so on. However, some genes show the classical continuous expression pattern and are seen at these sites all the time. One example is Beta-globin. Genes like these are relatively rare compared to those showing the pulse type expression but both are continuously on in there cell type. If elements of the beta-globin promoter is deleted then not only is overall expreesion decreased but it shows the pulse type expression.

One of the most interesting things is that some genes will co-localize to the same transcription factory more often than you expect by pure chance. What is more interesting is these genes can be separated by several megabases! or even be on different chromosome. Using the 3C and 4C assay you can join different pieces of DNA together from different parts of the genome that have transcribed within the same transcription foci. These have shown along with RNA FISH the physical movement of genes to the same place to be transcribed. One of the two Beta-globin alleles within a cell was found to enter the same factory with some other genes at a rate of ~25% with a background rate expected to be less than 2%. These gene’s promoters were searched and a simple motif was found: CCACC. This is actually a binding site for a regulator of Haem biosynthesis and haemoglobhin production called Eklf. When Eklf is knocked out the association between these genes stops! This transcription factor must recruit to these genes to the transcription factories it is located at. I can see two mutually exclusive models here (tell me what you think or extra ones to consider). Either 1) something, perhaps Eklf recruits genes to these sites and physically moves them there or 2) genes with this motif move to all transcription foci and only stay to be transcribed at ones that have Eklf present. I would guess the second is more likely but I see no evidence for either model at this time. Another question I would like answered is whether other or maybe all transcription factors work in this way. I think it is unlikely but perhaps that is the case!

One more interesting thing related to this is the story in B cells of mice. It has been shown that the proto-oncogene Myc is expressed in the same foci as immunoglobulin heavy chain (IgH) a very high proportion of the time. The interesting part is that these two genes have been show in many blood cancers to be translocated to be on the same chromosome so perhaps there is a link between transcription factories and cancer. Well that is what the people doing the research on it want to think. After all related to cancer equal more funding as I told a friend of mine earlier. A new lab has been set up by the post-doc who led most of the described research to explore the cancer link.

And I now realise one very important thing, I should have been writing my result section now I have a deadline as well as lab work, S#£!!%$! Hell!

Cameron S. Osborne, Lyubomira Chakalova, Jennifer A. Mitchell, Alice Horton, Andrew L. Wood, Daniel J. Bolland, Anne E. Corcoran, Peter Fraser (2007). Myc Dynamically and Preferentially Relocates to a Transcription Factory Occupied by Igh PLoS Biology, 5 (8) DOI: 10.1371/journal.pbio.0050192

Cameron S Osborne, Lyubomira Chakalova, Karen E Brown, David Carter, Alice Horton, Emmanuel Debrand, Beatriz Goyenechea, Jennifer A Mitchell, Susana Lopes, Wolf Reik, Peter Fraser (2004). Active genes dynamically colocalize to shared sites of ongoing transcription Nature Genetics, 36 (10), 1065-1071 DOI: 10.1038/ng1423


Catarina Vicente said...

And finally someone decides to post something- well done James, me and Melly will now be ashamed and start thinking about writing something as well.

I have a question for you- I'm sorry if it is a really silly one. When you say that these transcription factories are localised, do you mean only that any certain time transcription is only happening at certain positions, i.e. all the components of these factories move along the genome to transcribe certain sets of genes and certain times, or do they occupy a physical place in the chromosomes, and genes are moved in and out of it (I'm imagining a ribbon-style DNA being physically bent to reach these factoryes)- Am I trying to over dramatise it?

James Lloyd said...

Good question. I should have made what I said clearer. They are the sites where nearly all the RNAPII in the nucleus is found. Genes appear to loop out from the chromosome and enter them. I believe if you block transcription then these foci remain. I am not sure what the evidence is but apparently genes do not create them but move to them. I hope that mostly answers your question.

To Melly – I didn’t add references because A) I am lazy and B) because most of what I have written was presented at a conference and I don’t have reference for all of it but the co-localisation of B-globin and other and Myc and IgH are in the 2 I will add. I will try and add some photos to the post as well.

James Lloyd said...

what is interesting now is to hear that cells use replication foci attached to the nuclear matrix in a very similar way and this could be very related to these transcription foci.

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