DEEPERINTODNAMAURALANNERYSBIOLOGY…

DEEPER INTO DNA
B I O L O G Y T O D A Y
M A U R A C. F L A N N E R Y , DEPARTMENT EDITOR
BIOLOGY TODAY 563
make DNA that much more interesting, and I even want to impart some of this intricacy to my students. After all, it helps to explain how a mere 30,000 “genes” are responsible for the complexities of human life.
New Types of RNA
This rethinking of the definition of the gene has occurred in tandem with a rethinking of the role of RNA. It seems to me that RNA just keeps getting more interesting and more impor-tant—and more complicated. Here’s an interesting statistic: 63% of the mouse genome is transcribed into RNA, but only 1-2% of that genome is made up of exons that are then trans-lated into protein. For a molecular biology lover like myself, this is a wonderful and tantalizing statistic because it implies that there are other functions for the rest of that transcribed RNA, in all likelihood, regulatory functions. This makes sense, because there has to be a great deal of control to regulate something as complex as the human genome. It’s a tantalizing finding because it means that there is much still to be learned about how RNA functions.
Though much has already been discovered about RNA, the amount of information accumulating can be as mind-bog-gling as the new definition of the gene. I’ll just mention one study to give you a sense of what’s going on, and what we have to look forward to. MicroRNAs (miRNAs) and small interfer-ing RNAs (siRNAs) are 21 to 25 nucleotides long and repress gene expression by binding to mRNAs and preventing their translation into protein (Carthew, 2006). Now another family of short RNA sequences has been discovered that has a distinct function. They are 25 to 30 nucleotides long and are called piR-NAs because they interact with piwi protein which is involved in germ-line development. The piRNAs seem to have a role in regulating this development. One “surprise” here is that the DNA sequences transcribed into piRNAs are in regions of the genome that were thought not to be transcribed at all.
I put the word surprise in quotes, because it seems to be overused in molecular biology today where so many findings are labeled as surprising. This stems from the profundity of our ignorance. Everything is surprising because we know so little, making many discoveries weird and wonderful. Again, I don’t think I can present all these surprises to my students. Even if I could figure all this out for myself, do students really need to know about the subtleties of siRNAs, miRNAs, and piRNAs? On the other hand, they do need to know that the use of the information in the DNA is tightly controlled, and that RNA, in many different forms, and with many different functions, is a major factor in this control. Changing Roles
I have to admit that I began studying biology a long time ago, in the early 1960s when the importance of DNA was first sinking into the biological psyche. Francis Crick was just beginning to proclaim his idea of molecular biology’s “Central Dogma” that the information in DNA was used to make RNA, and then RNA was used to make protein. This was a one-way process, until the early 1970s when the first of the big “surpris-es” of molecular biology burst on the scene with the discovery of reverse transcriptase, an enzyme that converts RNA into DNA, thus weakening the “Dogma.” If you want some sense of what the early years of molecular biology were like, and are not lucky enough have experienced these years personally, you might want to read Horace Freeland Judson’s (1979) The Eighth Day of Creations: Makers of the Revolution in Biology. It’s huge, but it really gives a good sense of the people and ideas that were churning around at the time and how they panned out. My copy was a gift from my son years ago, and it remains one of the best presents he ever gave me (though I appreciate the jewelry too).
Even for those who can recall the 1960s and 1970s, Judson’s book is a good reminder of just how far molecular biology has progressed since then. He doesn’t get into gene cloning because this technology, which really opened up the eukaryotic genome to study, was just beginning to be devel-oped at the time. It’s also hard to believe now that in the late 1980s, the Human Genome Project (HGP) was just a gleam in the eyes of James Watson and some other biologists. It is in part because of the HGP and the other genomes which have been sequenced that present-day views on DNA and the gene are changing. One major research area right now deals with how DNA is used, and is called epigenetics, defined as “the layers of instructions that influence gene activity without alter-ing the DNA sequence” (Qiu, 2006, p. 143). In other words, epigenetics refers to how the information in the DNA is used in cells and organisms, and there are two major types of epi-genetic control. The DNA can be chemically altered, as when DNA is ethylated, which often represses gene activity. The sec-ond means entails changing the proteins that wrap DNA into chromatin. The primary proteins involved are the histones around which the DNA is wound to form nucleosomes. When the packing is tight, gene expression is less likely to occur than if the packaging is relaxed.
One source of information about human epigenetics has come from studies on identical twins. Even though they have the same genetic information, their bodies don’t necessarily function in exactly the same way. For example, one twin may develop cancer or diabetes or mental illness while the other doesn’t, so something else besides genes must be involved, namely how the genes are controlled and function. The genes may be the same but their activity isn’t, and these discrepancies increase with age. The differences in gene activity were three times greater in 50-year-old twins than in 3-year-old twins.
Studies of cancer in identical twins suggest that epigenetic factors may contribute as much to cancer development as do mutations in the DNA. This obviously has implications far beyond the world of identical twins. Wnk2, a gene that sup-presses tumor growth, is more frequently turned off by epigen-etic factors than by mutation. One good thing about this is that epigenetic changes are easier to reverse than genetic ones, so epigenetics may turn out to be a fruitful area in cancer research. For example as I mentioned earlier, one type of epigenetic control is the methylation of DNA that is related to turning off gene activity. The Food and Drug Administration has recently approved the drug Vidaza for treatment of preleukemia. It works by blocking methylation and thus stimulates the expres-sion of genes, including those that suppress cancer. Histones
While the HGP has focused attention on the genetic fac-tors causing disease, researchers now estimate that epigenetic factors make up to a 70% contribution to the likelihood of many diseases. In other words, it’s not just what happens to the
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BIOLOGY TODAY 565
process by unwinding the DNA and detaching the histone cores, thus taking nucleosomes apart in the area of the break so repair proteins have access to the DNA (Nussenzweig & Paull, 2006).
Research revealing an additional link between chro-matin remodeling and repair deals with topoisomerase IIß (TopoIIß), a protein that was originally found to be involved in DNA repair (Haince, Rouleau & Poirer, 2006). It causes a nick or single-stranded break in DNA to allow the excision of a defective sequence. Now the same protein has been found associated with chromatin remodeling. TopoIIß activates transcription by causing a break in the DNA so that the tight winding of the chromatin is relaxed and the transcription machinery can access the correct DNA sequence. This process has been identified at a number of gene sites so it may turn out to be a general mechanism. A link between repair and normal activity should not really come as too much of a surprise. After all, they both involve a reworking of the DNA and the frugality of the limited resources and complex needs of the cell almost demand that “tools” do double duty.
The case of TopoIIß is hardly the first time that an enzyme identified with one function later turns out to have another. This is yet another reminder of the depths of our ignorance of how cells work and of how narrow the windows of our knowl-edge and understanding are. We “see” one thing, discover one function, and immediately assume that this is the whole picture. How many times do we have to discover dual-acting proteins and other versatile molecules before we come to real-ize that such flexibility is the norm rather than a “surprising” anomaly in the chemistry of life.
Epigenome Project
In order to make more progress in epigenetics, some researchers are calling for an international human epigenome project or IHEP as a successor to the HGP (Qiu, 2006). One problem in following through on this idea is that its scope could make the HGP look minuscule. While all the cells in an individual have the same genetic makeup, epigenetics var-ies from one cell type to another within one person, to say nothing of the differences across individuals. So it might make more sense to break efforts down into focusing on different tissues, such as blood, muscle, etc. But even this is still daunt-ing. A European Human Epigenome Project Consortium was formed several years ago, and its approach is to look at the epigenetics of individual chromosomes. It will soon publish epigenetic data on three chromosomes, including 22 which is involved in Down’s Syndrome.
If epigenetic research is seen by experts as overwhelming, where does that leave biology teachers and their students?
I would argue that we end up in an enviable position. We don’t have to deal with the funding and politics of epigenome research but we can dip into the results. In our teaching, we don’t have the time or the expertise to get into too much of the specifics but I think it’s important for students to appreci-ate the significance of this work. Not only could it ultimately be important to human health, but it is a continuation of the HGP story and helps to put this project into perspective. It makes me feel ancient to realize that the HGP is now an old story: It’s been over five years since the first version of the human genome was published. Where has it led us? We can become discouraged that it hasn’t resulted in huge advances in understanding disease, but on the other hand, it has greatly advanced epigenetic research.
Having the DNA sequence available made work like that on discovering the positions of nucleosomes possible. Sure, things are very messy right now in the world of epigenetics, but I think this in itself is a good thing for students to appreci-ate. They don’t like it when there isn’t a clear answer available to a scientific question, and in epigenetics there are definitely more questions than answers. But this is the reality of scien-tific research. In addition, this makes slogging through at least a little of the research fun. No one, not even the experts, know quite where the answers lie. This is real science: groping in the dark, and the prevalence of this darkness before the dawn of discovery is probably the most important thing students need to come to appreciate about science.
Roald Hoffmann (2006), a Nobel Prize-winning chemist and published poet, recently wrote an article on the impor-tance of metaphor in understanding science: Metaphorical language can make the complexities of science available to all by creating meaningful images. I was reminded of this while reading Jane Qiu’s (2006) article on the epigenome. She compares epigenetics to an unfinished symphony: “If the DNA sequence of the genome is like the musical score of a sym-phony, then the epigenome is like the key signatures, phrasing and dynamics that show how the notes of the melody should be played” (p. 144). Though I am practically tone deaf and have absolutely no musical ability, I really like this metaphor. From the little I know about music, I realize that the score is only the beginning, that to create a great performance the conductor and the musicians have to use that score, work with it, interpret it, and build on it. This seems to be what happens to the DNA score through epigenetic controls. The conductor Robert Spano describes all that goes into making music, and he admits that much of it is impossible to put into words (Davidson, 2006). With working out epigenetics, it is impossible for us to convey all its complexities to our students but we can at least give some hint of just how beautiful this symphony is by playing just a few bars, giving just a couple of details, from time to time.
References
Becker, P. (2006). A finger on the mark. Nature, 442, 31-32. Carthew, R. (2006). A new RNA dimension to genome control. Science, 313, 305-306.
Davidson, J. (2006, August 21). Measure for measure. The New Yorker, pp. 60-69.
Haince, J., Rouleau, M. & Poirer, G. (2006). Gene expression needs a break to unwind before carrying on. Science, 312, 1752-1753. Hoffmann, R. (2006). The metaphor, unchained. American Scientist, 94, 406-407.
Judson, H.F. (1979). The Eighth Day of Creation: Makers of the Revolution in Biology. New York: Simon and Schuster.
Keller, E.F. & Lloyd, E. (Editors). (1992). Keywords in Evolutionary Biology. Cambridge, MA: Harvard University Press. Nussenzweig, A. & Paull, T. (2006). Tails of histones lost. Nature, 439, 406-407.
Pearson, H. (2006). What is a gene? Nature, 441, 399-401.
Qiu, J. (2006). Unfinished symphony. Nature, 441, 143-145. Richmond, T. (2006). Predictable packaging. Nature, 442, 750-752. Segal, E. (2006). How strings of DNA use protein positions to wrap up.
Nature, 442 (7104), xi.
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