It Comes with the Territory
A lot of what we know about transcription and gene regulation in eukaryotes has been from experiments in test tubes. The problem of course, is that test tubes aren’t the same as our cells. We have things like nuclei that aren’t homogeneous; there’s all sorts of stuff in there! Lamins, other nuclear cytoskeletal elements, histones, large loops of chromatin (DNA and the proteins stuck to it), and so on. Clearly, nuclei aren’t just bags of DNA and protein.
A lot of research has gone into trying to figure out how DNA is organized in the nucleus, and what that has to do with gene expression. Some people like to call this field “cytogenetics.” We now know a lot about how histones move and shift along DNA when genes turn on and off, but a lot less is known about higher order chromatin structures. One idea about gene expression is that of “chromatin territories” and “transcriptional factories.” A good review paper on the concept is appeared in Nature Reviews Genetics in 2001;1 if that’s too long for you, here’s bullet point summary of the review (kind of a sad concept, if you ask me).
The basic idea is that chromosomes occupy particular mutually exclusive spatial “territories” of the nucleus. An idea that kind of got melded with that theory (but which is actually still a separate idea) is the “transcriptional factory” or “interchromatin compartment.” When genes turned on, some scientists have thought that the DNA of that gene moves to special parts of the nucleus enriched in the proteins needed to transcribe, splice, and explore the genes.
This is a really cool picture from that review paper showing why so many biologists think that chromatin territories might be the real thing, even if the evidence for them is still a little vague. It shows a chicken cell nucleus, with each chromosome “painted” a different color by combinatorial immunofluorescence:
One problem with the theory of chromosomal territories and with this sort of visualization is that it’s unclear whether the nucleus just happens to form like this spontaneously, or whether it’s actually regulated to be this way. I’d argue for the former; bacteria, for example, may spontaneously segregate their chromosomes simply due to their polymer physics. Here’s a paper (open access!) summarizing the results of that research.2
In this figure from that paper, the bacterial chromosomes start to segregate spontaneously as the DNA replicates. There’s no specific transport or regulatory mechanism necessary other than rigid confinement of the DNA polymers. It looks too similar to the situation above in the chicken nucleus to dismiss it outright as an explanation, I think.
The other related theory is the “transcriptional territory”, which is the idea that genes that are turned on migrate to certain areas of the nucleus that are enriched for transcription factors, RNA polymerase II, splicing proteins, and export factors. A lot of the evidence for this comes from microscopy, such as this figure from the review paper:
The red staining is a splicing factor, SC-35, and the green is the chromatin labeled with GFP-tagged H2B. It’s clear that there’s certainly some sort of protein aggregate in the nucleus, but whether it’s functional is certain up for definitive proof. Another good review paper for transcriptional factories is Chakalova et al., again in Nature Reviews Genetics.3
Next time, I’ll dig into a new paper from Molecular Cell that seems to strike a blow against the whole “transcriptional factory” idea.
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1. Cremer, T. and C. Cremer. (2001) Nat Rev Gen 2, 292-201.
2. Jun, S. and B. Mulder. (2006) PNAS 103, 12388-12393.
3. Chakalova et al. (2005) Nat Rev Gen 6, 669-677.
