Form influences function

UTRECHT, The Netherlands—It's easy to think of genomics intwo-dimensional terms, particularly with all the data on flat screens,expressed in characters and colors, and to only think "three dimensionally" interms of influences on the genome from things like the environment and otherextra-genomic sources. But it turns out, as noted by research publishedrecently in Nature, thatthree-dimensional shape of DNA and position of genes within it have a lot to dowith stems cells and their function in the genome, and not just the sequence ofgenes.

As Dr. Wouter de Laat of the Hubrecht Institute in Utrecht,The Netherlands, who specializes in making DNA folding in the cell nucleusvisible, 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 DNAstrings in embryonic stem cells are folded in a unique manner and in a mannerthat 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 theydo not change into other types of cells.

As the researchers note in the Nature paper of DNA's three dimensions, "In recent years, severaltechnological advances have made it possible to delineate the three-dimensionalshape of the genome. Spatial organization of DNA has been recognized as anadditional regulatory layer of chromatin, important for gene regulation andtranscriptional competence. In somatic cells active and inactive chromosomalregions are spatially segregated. Recently, the genome was further shown to besubdivided into evolutionarily conserved topological domains."

In terms of stem cell genetics, the researchers point outthat stem cell factors are responsible for the special DNA folding in embryonicstem cells. These are proteins that can only be found in stem cells and withwhich normal cells can be reprogrammed into stem cells, they note, and withoutthese proteins, stem cells lose their unique DNA folding. The proteins attachto DNA strings in various places and "pull" the strings together.

While de Laat admits, "we don't know exactly why these geneshave to be so close to each other," he theorizes that it might be "entirelypossible that this will allow the stem cell genes to be sequenced in animproved and more stable manner. It makes stem cells more robust."

Previous research had focused on the sequence of the geneticletters in the DNA as key, but these findings by de Laat and his team suggestthat the three-dimensional organization of DNA strings is also criticallyimportant and that genes with a comparable role may need to literally be closeto 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 controllayer."

As the authors note in the paper, "It has been suggestedpreviously that transcription factors position tissue-specific and co-regulatedgenes in somatic cells. However, in contrast to previous studies, we validatedthis concept by comparing genome-wide contact maps only changes specificcontacts while the overall folding of chromosomes remains intact is inaccordance with a recently proposed model for chromosome topology. This'dog-on-a-lead' model predicts that chromosomes are dominant over theirindividual segments (genes, domains, enhancers) in dictating the overall shapeof the genome, but that segments can search the nuclear subvolumes they occupyfor preferred contact partners. There is accumulating evidence thatstochastically determined nuclear environments can influence thetranscriptional output of resident genes, leading to cell-to-cell variability.We propose that the observed spatial clustering of pluripotency factor bindingsites in pluripotent stem cells enhances the transcription efficiency of nearbygenes and thereby contributes to the robustness of the pluripotent state."

In the long run, according to de Laat, the findings from thestudy are a significant contribution to the growing area of regenerativemedicine and could lead to new insights into the origins of diseases.

The findings of the team were published in the July 24 issueof Nature in a paper titled "Thepluripotent genome in three dimensions is shaped around pluripotency factors."

The Hubrecht Institute is a research institute of the Royal Netherlands Academyof Arts and Sciences and collaborates closely with University Medical CenterUtrecht.