an 2 meters, or 6 feet, per cell) could pack into a nucleus only 6/1,000,000 of a meter in diameter (smaller than the diameter of a human hair).
Eventually, studies showed that DNA decreases in length when regions of about 166 base pairs wrap like twine around small proteins to form complexes known as nucleosomes . A short stretch of non-wound DNA falls between each nucleosomal unit, the result looking a bit like a string of beads. In such a configuration, a 1-meter (3-foot) strand of DNA is reduced to 14 cm (about 6 inches). This shortened strand then coils even more, until an X-shaped chromosome in a dividing cell measures roughly 1/10,000 the length of the DNA strand it contains!
The “fractal globule” (aka ramen noodles)
So what does the 3-dimensional model of the nucleus, as seen in the Genome Ball, have to do with all this?
One of the most important discoveries in genome biology has been the demonstration that genomes are non-randomly organized in the nucleus.
Even though chromatin looks like long straggly threads, it is amazingly well organized: Thanks to the organized coiling of chromatin, genes are able to interact with the DNA regions that regulate them.
The genome is organized into “distinct regions of open and closed chromatin regulatory domains,” explains Dr. Laura Elnitski, senior investigator at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health. Put more simply, chromatin that is less active in a given cell type, or chromosomes containing few genes, are located just inside the nuclear membrane; but more active chromatin (for example, a gene coding for insulin in healthy pancreatic cells), and chromosomes carrying many genes, occupy the center of the nucleus. Overall, the nuclear location of specific genes correlates with their activity in a given cell.
Erez Aiden (who spearheaded the Genome Ball project) also discussed chromatin organization in his prize-winning essay in Science: “Loci on the same chromosome – even at opposite ends – interact more than loci on different chromosomes.” And within individual chromosomes, “open [active] chromatin interacts more with open chromatin and closed with closed,” wrote Aiden. In short: Genes have more interactions with regions on their own chromosome; and within any given chromosome, active regions group together with other active regions, while quiet or gene-poor areas group with other quiet regions.
Aiden had found a paper theorizing that long polymers – DNA is a good example – are able to form very tight coils with no knots, “a configuration known as the fractal globule.” One of the most striking characteristics of the fractal globule is that it can be folded and refolded without disturbing the rest of the condensed polymer.
The fractal globule is easy to explain to graduate students because it closely resembles the only food we can afford: ramen, said Aiden.
Uncooked, the noodles don’t contain any knots. Even when partially cooked, they don’t get tangled in the cooking pan. However, ramen noodles do become tangled after cooking, whereas chromatin stably maintains its unknotted state throughout interphase – the period between cell divisions when chromatin in the nucleus uncoils. In that condensed but non-knotted configuration, sections of chromatin that are far apart on the long strands may be brought into proximity. Thus, interactions between chromatin on the same chromosome, or between sections with similar properties or functions, are made possible by the way chromatin is organized in the interphase nucleus.
These are but a few of the innovative and complex understandings that inspired the creators of the Genome Ball (for more information about the 3-D printing of the Genome Ball displayed at the exhibition, see the feature article “Super 3D Model: How the Genome Ball Was Created” on this website). Our knowledge of the nucleus has come a long way in the 332 years since Leeuwenhoek. But, as Aiden’s Science essay concluded: “at the fringes of our maps the world is full of surprises.”
The same is certainly true of the nucleus.