You know those unpopular kids at the edge of the playground, excluded from playing with the others? It appears this situation is no different for genes, according to researchers from the Netherlands.
In eukaryotic cells all the genetic material resides in the nucleus, which is separated from the surrounding cytosol by a nuclear membrane. The nuclear lamina lines this membrane on the inner side and consists of a meshwork of different proteins, mainly lamins. It provides mechanical support for the membrane and is involved in chromosome organization.
Electron Microscopy image of the Nuclear Membrane (Martin Goldberg)
The organization and location of chromosomes plays a large role in determining which genes are active, and which are silent. But whereas it has become easier and easier to sequence DNA, much has remain unknown about the three dimensional organization of chromosomes, and how it affects the transcription (activity) of genes.
Last year, Lars Guelen and his colleagues made a map of chromosomal regions that interact with the nuclear lamina. With this map, they could exactly pinpoint which parts of the chromosome are associated to the lamina. In other words, these ‘lamina associated domains’ (LADs) are located at the periphery of the nucleus (at the edge of the playground).
How did Guelen and colleagues make this map? They fused components of the nuclear lamina, the lamins, to a DNA adenosine methylase. In this way, the lamin parts of the fusion proteins still associate with the nuclear lamina, while the DNA adenosine methylase starts methylating adenosine in DNA. Since adenosine normally does not get methylated in eukaryotes, all methylated adenosines came from the fusion protein, and are therefore associated with the nuclear lamina.
The researchers found some very sharp transitions between the LADs and non-LAD regions, as you can see below. The boundaries are remarkably well defined! The story continues: the number of genes within these LADs was significantly lowered, compared to regions outside LADs. Not only are there less genes within LADs, they’re also transcribed less often, as there were depleted of activating histone modifications and RNA polymerase II. Additionaly, the insulator protein CTCF was found at the LAD borders. All in all this is some convincing evidence for a repressive role of LADs!
Lamin binding ratios on chromosome 4 of human fibroblasts. (figure from paper)
In short, if you’re a gene looking for some transcription, it’s best to avoid the periphery, and find a nice spot in the centre. It will be interesting to see whether LADs have a regulatory role. Do chromosomic regions become LADs during differentiation for example? And if so, what is the mechanism which destines some genes to be the unpopular kids on the block?
Guelen, L., Pagie, L., Brasset, E., Meuleman, W., Faza, M., Talhout, W., Eussen, B., de Klein, A., Wessels, L., de Laat, W., & van Steensel, B. (2008). Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions Nature, 453 (7197), 948-951 DOI: 10.1038/nature06947
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Oh wow, that is very pretty data. I wonder if that’s an active process of a passive one; if non-transcribed genes get packaged or shunted off to the laimina, or whether they just sort of end up hanging around there because all the exciting stuff is going on in thhe middle of the nucleus.