We’re enlightened–continually–by Carl Zimmer, this time writing in the New York Times, describing the hope-filled birth of a word, long-since burdened to a life of heavy lifting.
[Gene] was coined by the Danish geneticist Wilhelm Johanssen in 1909, to describe whatever it was that parents passed down to their offspring so that they developed the same traits. Johanssen, like other biologists of his generation, had no idea what that invisible factor was. But he thought it would be useful to have a way to describe it.
Many people will assume the “invisible factor” to be DNA. Technically, this is correct, it’s all nucleotides after all, but to think of a gene–all the information needed for protein design–as a single sequence of DNA is incorrect. For example, every cell has the coding sequence of every gene and therefore the ability to manufacture any protein in our body. When a cell makes a protein, that protein’s nucleotide correlate must first, to paraphrase Madonna, express itself. (Happily, genes are much less prolifigate than the Queen of Pop, save for those big genetic blunders under which teratomas arise.)
What’s this about censoring expression? Zimmer has this to say,
But it turns out that the genome is also organized in another way, one that brings into question how important genes are in heredity. Our DNA is studded with millions of proteins and other molecules, which determine which genes can produce transcripts and which cannot. New cells inherit those molecules along with DNA. In other words, heredity can flow through a second channel.
These “millions of proteins and other molecules” are themselves no more than the expression of proximal and distal DNA sequences. But as Zimmer points out, a second-channel mechanism above the level of DNA is at work. Fighting the urge to invoke strange loops, lets take a closer look at some of the ways these proteins and molecules regulate gene expression.
Take chromatin for instance; it’s of those “millions of proteins and molecules.” If DNA were spaghetti, then chromatin would be the twirling tines of a fork that wrap it up (three times) during expression. This looped-up DNA–otherwise known as an altered spatial organization–is under specific and temporal expression control. A master regulator of body segmentation in the Drosophila, the Bithorax complex, falls into this category of expression regulation via spatial organization of DNA.
What’s fascinating is when something upsets the setup. In humans, disruption of chromatin complexes can lead to overexpression and ill-timed expression of genes, which yields to both undifferentiated and unchecked cell growth–in a word, cancer. Fruitful then would be the study of the mechanism and regulation of chromatin complex function so as to better understand how higher order chromatin structure influences the intricately orchestrated expression programs needed for proper development and differentiation. And if not in humans then zebrarfish, and if not zebrafish, Drosophila.
Not suprisingly, the best studied chromatin domain to date happens to be Drosophila’s gypsy chromatin insulator. It’s a big complex of DNA wound around three proteins. There’s some evidence to suggest that these DNA binding proteins bridge distant DNA sequences, which are then trascribed in toto. Aggregates of these complexes can form even higher order scaffolds of looped DNA–groups of genes in effect working as a whole. What’s interesting is how these mighty architectures can be undone by a simple structure: RNA.
Scientists think RNA indirectly interacts with DNA binding proteins. Deactivating the RNA–RNA silencing–regulates expression of DNA at the protein level. Researchers at Harvard Medical School† studying the gypsy chromatin insulator found evidence for this when they biochemically silenced RNA, and again when they found mutations in Drosophila genes encoding RNA silencing components. Now they want to express the gypsy chromatin insulator in vitro–in cell culture–then induce double-strand RNA knockdowns to find what new and exciting factors are involved.
Let’s review: DNA->RNA->(protein<-RNA)->DNA->RNA… Or something like that.
nod to EvolutionBlog.
†
1. Gerasimova TI, Lei EP, Bushey AM, Corces VG Coordinated Control of dCTCF and gypsy Chromatin Insulators in Drosophila. Mol Cell (28): 761-72, 2007.
2. Caretti G, Lei EP, Sartorelli V The DEAD-Box p68/p72 Proteins and the Noncoding RNA Steroid Receptor Activator SRA: Eclectic Regulators of Disparate Biological Functions. Cell Cycle (6), 2007.
3. Lei EP, Corces VG A long-distance relationship between RNAi and Polycomb. Cell (124): 886-8, 2006.
4. Lei EP, Corces VG RNA interference machinery influences the nuclear organization of a chromatin insulator. Nat Genet (38): 936-41, 2006.
5. Pai CY, Lei EP, Ghosh D, Corces VG The centrosomal protein CP190 is a component of the gypsy chromatin insulator. Mol Cell (16): 737-48, 2004.
It was fun to read the article in the NYT because I know most of the people quoted in it. I particularly like David Haussler’s quote “Our genome is littered with the rotting carcasses of these little viruses that have made their home in our genome for millions of years”
Quite the graphic way of saying it. I might have to steal that.
T he way I like to look at it is that transposons are just another mutational mechanism. As far as the definition of gene, I think people (not just Carl) are understating the previous controversy and overstating the effect of the new information.
It is quite a big deal that epigenetic marks are more prevalent and influential than we thought, but that’s basically because the technology to investigate them at a large scale is only now being developed. Various forms of epigenetic mark have been known about for quite a long time. They weren’t really analyzed in a genome-wide way because before nobody had the money or the technology to do it.
I guess some people felt epigenetic regulation, post-transcriptional regulation, and splicing were unimportant because they couldn’t see them with their microarrays and RT-PCR, but as long as we’ve known about those things people have arguing that they were very important.
I think genome scientists often think they are the pioneers in every field because they’ve found something revolutionary they never heard before. When usually people in less well funded fields have been plugging away studying the same things for years and years. They may not have had the amount of data that genome scientists have, but most of the time they have
some idea of what’s going on.
Evolutionary biologists at least have been arguing about the definition of a gene almost as long as they’ve been arguing about the definition of a species. Our idea of exactly what genes are and how complex they are is definitely changing, but it’s a gradual evolution, rather than a saltational shift. I like Tom Gingeras’s quote “Its almost a recapture of what the term was originally meant to convey”. Exactly. It was never a hard and fast definition, except maybe to some high-school biology teachers (and apparently some genomicists).
I’m conflicted about the article. I enjoyed reading it, and Carl Zimmer definitely presented some of the complexity involved. The problem is it seemed to me to fall into the classic science writer (and scientist) trap of over-sensationalizing. To Carl’s credit it’s very hard to avoid that when you’re talking to genome scientists. I’m not sure if there’s a field of science with more successful sensationalizers than genome biology. (Maybe space science or something like that, NASA’s got to have some of the best PR in science).
As far as evolution goes I’m still not convinced that epigenetics is something so shocking. I view it as yet another layer of regulation. It is pretty nifty that epigenetic marks can persist across a generation, but I don’t think that many people are seriously arguing that it’s persistent enough to be the carrier of long term evolutionary information.