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Form influences function
UTRECHT, The Netherlands—It's easy to think of genomics in two-dimensional terms, particularly with all the data on flat screens, expressed in characters and colors, and to only think "three dimensionally" in terms of influences on the genome from things like the environment and other extra-genomic sources. But it turns out, as noted by research published recently in Nature, that three-dimensional shape of DNA and position of genes within it have a lot to do with stems cells and their function in the genome, and not just the sequence of genes.
As Dr. Wouter de Laat of the Hubrecht Institute in Utrecht, The Netherlands, who specializes in making DNA folding in the cell nucleus visible, boils it down: "Stem cell genes seek each other in the cell nucleus," and he calls it "a new way of looking at DNA."
What de Laat and his colleagues did was to show that DNA strings in embryonic stem cells are folded in a unique manner and in a manner that dictates that all of the stem cell genes are located close to each other. The activity of these genes ensures that stem cells remain stem cells and they do not change into other types of cells.
As the researchers note in the Nature paper of DNA's three dimensions, "In recent years, several technological advances have made it possible to delineate the three-dimensional shape of the genome. Spatial organization of DNA has been recognized as an additional regulatory layer of chromatin, important for gene regulation and transcriptional competence. In somatic cells active and inactive chromosomal regions are spatially segregated. Recently, the genome was further shown to be subdivided into evolutionarily conserved topological domains."
In terms of stem cell genetics, the researchers point out that stem cell factors are responsible for the special DNA folding in embryonic stem cells. These are proteins that can only be found in stem cells and with which normal cells can be reprogrammed into stem cells, they note, and without these proteins, stem cells lose their unique DNA folding. The proteins attach to DNA strings in various places and "pull" the strings together.
While de Laat admits, "we don't know exactly why these genes have to be so close to each other," he theorizes that it might be "entirely possible that this will allow the stem cell genes to be sequenced in an improved and more stable manner. It makes stem cells more robust."
Previous research had focused on the sequence of the genetic letters in the DNA as key, but these findings by de Laat and his team suggest that the three-dimensional organization of DNA strings is also critically important and that genes with a comparable role may need to literally be close to each other.
According to de Laat, "This is a new way of looking at DNA. The spatial organization of the DNA actually forms an additional control layer."
As the authors note in the paper, "It has been suggested previously that transcription factors position tissue-specific and co-regulated genes in somatic cells. However, in contrast to previous studies, we validated this concept by comparing genome-wide contact maps only changes specific contacts while the overall folding of chromosomes remains intact is in accordance with a recently proposed model for chromosome topology. This 'dog-on-a-lead' model predicts that chromosomes are dominant over their individual segments (genes, domains, enhancers) in dictating the overall shape of the genome, but that segments can search the nuclear subvolumes they occupy for preferred contact partners. There is accumulating evidence that stochastically determined nuclear environments can influence the transcriptional output of resident genes, leading to cell-to-cell variability. We propose that the observed spatial clustering of pluripotency factor binding sites in pluripotent stem cells enhances the transcription efficiency of nearby genes and thereby contributes to the robustness of the pluripotent state."
In the long run, according to de Laat, the findings from the study are a significant contribution to the growing area of regenerative medicine and could lead to new insights into the origins of diseases.
The findings of the team were published in the July 24 issue of Nature in a paper titled "The pluripotent genome in three dimensions is shaped around pluripotency factors."