You may have heard that all the DNA in your body, if stretched out, could reach to the Sun and back more than 70 times. What is even more amazing is that all this DNA occupies only a tiny fraction of the space within your body — it is packed away inside the tiny nucleus of each cell. Furthermore, the DNA is not merely packed away and sitting idly; rather, it is a dynamic molecule taking part in several active processes including gene expression and cell division. Three new scientific papers have been published in recent weeks that reveal exquisite patterns of design in the DNA and nucleus in which it is housed.
Turning Off a Chromosome
The human genome is organized in 23 pairs of chromosomes. Most of the pairs are of similar length, but in the final 23rd pair, the first chromosome — designated X — is much longer than the second chromosome — designated Y. That is not the only unique characteristic of the 23rd pair. These so-called sex chromosomes differ between the genders. While males have both an X and Y chromosome, females have two X chromosomes. As if to avoid a double dose of X chromosome genes, females inactivate one of their two X chromosomes during embryonic development. As for which of the two X chromosomes is inactivated, this appears to be done randomly in each cell. This means that females, unlike males, have two different functional genomes operating in their bodies, making for a fascinating twist to female genetics. That is, in some cells of the female, the first X chromosome is active whereas in the remainder of the cells the other X chromosome is active. A classic example is the colorful calico cat whose two X chromosomes code for two different colors.
Exactly how the developing female embryo inactivates one of the X chromosomes has not been well understood. What has been clear is that the story involves a region on the X chromosome itself, and information in that region that codes for a long RNA molecule, known as Xist. The name Xist stands for X-inactive specific transcript, a direct reference to its function of inactivating the X chromosome. But a genetic region that, ultimately, causes the inactivation of the entire chromosome must be handled very carefully. It is present on all X chromosomes but causes inactivation not of the single male X chromosome, and not of one of the two female X chromosomes. Importantly it causes inactivation only of the other female X chromosome.
In addition to the fact that Xist must be very carefully controlled, new research1 is shedding light on how this single molecule can produce such a significant result. While it seemed that a very large number of Xist molecules must be required to inactivate the much larger X chromosome, the researchers studied mouse embryonic stem cells and found that only about one hundred Xist’s are required. The Xist’s, operating in pairs, recruit a large number of proteins. The result is about 50 complexes, each consisting of two Xist’s and an army of proteins, spaced along the X chromosome. Some of the proteins twist and condense the overall chromosome, compressing it so that most of the genes are close to one of the 50 complexes. Other proteins act to silence those nearby genes, thus essentially inactivating the entire X chromosome. Obviously, there are many important, coordinated, steps in this inactivation process, allowing for a small number of Xist’s to manage this big job. As the paper’s lead author remarked, “It was kind of shocking to us that from just 50 sites, Xist manages to silence a thousand genes.”2
Three Dimensional Structures Within the Nucleus
X chromosome inactivation is not the only function that RNA molecules perform in the nucleus. They also, for example, help to maintain the overall three-dimensional structure of the various macromolecules in the nucleus, including the DNA. This is important because otherwise in the crowded nucleus, molecules can inadvertently chemically bond, or link, to one another. DNA crosslinking, for example, can result from environmental toxins and radiation. Such crosslinking, whether between DNA or other molecules, can cause cell death and is the goal in some chemotherapies. But crosslinking also is proving to be a valuable research tool. As another new paper reports,3 crosslinking is now being used, along with several other complicated steps, to map out the three-dimensional structure of the DNA, various RNAs, and many proteins, within the nucleus. Simply put, the general idea is to link together molecules that are in close proximity. The cell is then broken down into clusters of linked molecules which can be identified and mapped out to reconstruct the structures within the nucleus.
The researchers found the certain RNA molecules serve to recruit and organize other RNA and protein molecules. Those recruited RNA and protein molecules, which otherwise would randomly move about, then serve important regulatory roles in accessing and processing the DNA’s genetic information. The researchers also found that several high-concentration territories are formed within the nucleus, where these molecules cluster and function. As the paper explains, the organizing RNA molecules “recruit diffusible RNA and protein regulators into precise 3D structures.” What we are seeing is a much more detailed, elegant, and exacting picture of the nucleus than textbooks have ever envisioned.
A Very Special Protein
The problem of organizing and maintaining the molecular structures within the nucleus becomes even more intriguing when one considers cellular division. When a cell divides, producing two daughter cells, the precise 3D nucleus structure discussed above must somehow be reestablished in the new cells. Certain proteins have been known to be important in this process, and another new study4 has now identified a single protein that is particularly important in this cell division process. The protein, called lamin C, is, according to the paper, “uniquely required for large-scale chromosome organization,” and “global 3D genome organization” in the daughter cells.
During the process lamin C is phosphorylated, meaning a phosphoryl group is attached by special proteins. The phosphoryl group is removed when lamin C is done with its job, which is just one part of a larger, more complex process. As the lead researcher explained, “There is this exquisite choreography of the different lamin proteins and DNA to get things just as they should be.”5
Beyond this exquisite choreography, the crucial role of lamin C highlights another hallmark of design; namely, the teleology implicit when a part is required for its own production. Because lamin C, a protein, is produced by cellular protein synthesis. That is a process that begins with the genome in the nucleus, which is maintained by lamin C. In other words, lamin C is required for the production of lamin C.
These three studies of the structures within the cell’s nucleus continue to reveal a natural world that gives evidence design in many different ways.
- Yolanda Markaki et al, “Xist nucleates local protein gradients to propagate silencing across the X chromosome,” Cell (2021).
- Sarah Williams, “Xist marks the spot: How an RNA molecule silences the X chromosome,” PhysOrg, Nov. 12, 2021.
- Quinodoz SA, Jachowicz JW, Bhat P, Ollikainen N, Banerjee AK, Goronzy IN, Blanco MR, Chovanec P, Chow A, Markaki Y, Thai J, Plath K, Guttman M. RNA promotes the formation of spatial compartments in the nucleus. Cell. 2021 Nov 11;184(23):5775-5790.e30. doi: 10.1016/j.cell.2021.10.014. Epub 2021 Nov 4. PMID: 34739832.
- Wong, X., Hoskins, V.E., Melendez-Perez, A.J. et al. Lamin C is required to establish genome organization after mitosis. Genome Biol 22, 305 (2021).
- Science Daily, “Mouse cell studies show that correcting DNA disorganization could aid diagnosis and treatment of rare inherited diseases,” November 14, 2021.