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.