Encode Project Opens Unimagined Vistas of Discovery

The more we learn about the mechanisms of life, the more we discover there is yet to be learned. Results from the "Encode Project" have reminded us of how little we know about the human genome and epigenome -- while at the same time opening the door to previously unimagined possibilities for discovery and scientific advancement. With this new opportunity for acquiring vast new knowledge, the road to longer lifespans and better brains has just gotten wider, smoother, and more solid.

We are just beginning to learn how our genes are regulated on a moment to moment basis. If we are to achieve our goals for longer, more capable, and more fulfilling lives, we will have to use all of our wits and tools -- and develop a lot of new ones.

When the Human Genome Project revealed that only around two percent of the genome is made up of protein-coding genes, it was suggested that the rest was made up of "junk DNA". The unsatisfactory conclusion left many geneticists skeptical, and Encode's findings now prove beyond doubt that the theory was way off mark.

The new research instead shows that 80 percent of the 98% unaccounted for has some kind of biochemical function, with 10,000 genes tasked with regulating the DNA responsible for coding proteins -- these 10,000 are responsible for building single-strand RNA molecules that regulate the 20,000 protein-coding genes. The mass of otherwise unaccounted for DNA actually represents a series of around four million "switches" that regulate other genes, and around nine percent of DNA helps code these switches (the figure could end up being nearer 20 percent, however).

...Encode has its work cut out. Having identified these millions of genes and investigated what turns them on an off, the team needs to track how they are connected and which genes they control. This will prove particularly challenging, considering genes in the three-dimensional genome are not mapped out in a straightforward manner -- a gene-controlling switch could be located somewhere entirely different from the gene it controls. Understanding the complex circuit route is key to understanding the human genome while, according to Birney, identification of the entire genome is only about 10 percent done.

... _Wired.co.uk

A User's Guide to the ENCODE Project (PDF)

First came the Human Genome Project, focusing on protein-coding genes. Next came the Encode Project, focusing on genes that regulate other genes. Now we will have to learn how the entire complex works together, for the sake of a better human future.

Steps Toward the Mastery of DNA Based Life

Synthetic biologists are hard at work designing ways for microbes to produce new drugs, fuels, high value chemicals, and other important products to facilitate an abundant human future. Much of this work is being held back by the difficulty of moving beyond the primitive prokaryote bottleneck of bacterial cell signaling and transcription factors -- toward the mastery of more complex eukaryotic cells and gene expression found in yeast and higher organisms.

MIT's Timothy Lu and his collaborators at Boston University, have created 19 new transcription factor which work in (eukaryotic) yeast. They are hoping that some of them will also work in algae and other higher eukaryotic organisms.

So far, most researchers have designed their synthetic circuits using transcription factors found in bacteria. However, these don’t always translate well to nonbacterial cells and can be a challenge to scale, making it harder to create complex circuits, says Timothy Lu, assistant professor of electrical engineering and computer science and a member of MIT’s Research Laboratory of Electronics.

...“If you look at a parts registry, a lot of these parts come from a hodgepodge of different organisms. You put them together into your organism of choice and hope that it works,” says Lu, corresponding author of a paper describing the new transcription factor design technique in the Aug. 3 issue of the journal Cell. _MITNews_via_NBF

The project is part of a larger, ongoing effort to develop genetic “parts” that can be assembled into circuits to achieve specific functions. Through this endeavor, Dr. Lu and his colleagues hope to make it easier to develop circuits that do exactly what a researcher wants.

...Recent advances in designing proteins that bind to DNA gave the researchers the boost they needed to start building a new library of transcription factors. In many transcription factors, the DNA-binding section consists of zinc finger proteins, which target different DNA sequences depending on their structure. The researchers based their new zinc finger designs on the structure of a naturally occurring zinc finger protein. “By modifying specific amino acids within that zinc finger, you can get them to bind with new target sequences,” Dr. Lu says.

The researchers attached the new zinc fingers to existing activator segments, allowing them to create many combinations of varying strength and specificity. They also designed transcription factors that work together, so that a gene can only be turned on if the factors bind each other.

Such transcription factors should make it easier for synthetic biologists to design circuits to perform tasks such as sensing a cell’s environmental conditions. The researchers built some simple circuits in yeast, but they plan to develop more complex circuits in future studies. “We didn’t build a massive 10- or 15-transcription factor circuit, but that’s something that we’re definitely planning to do down the road,” Dr. Lu says. “We want to see how far we can scale the type of circuits we can build out of this framework.”

The researchers are also planning to try their new transcription factors in other species of yeast, and eventually in mammalian cells including human cells. “What we’re really hoping at the end of the day is that yeast are a good launching pad for designing those circuits,” Dr. Lu says. “Working on mammalian cells is slower and more tedious, so if we can build verified circuits and parts in yeast and then import them over, that would be the ideal situation. But we haven’t proven that we can do that yet.” _Genetic Engineering News

Cell article abstract

The Mystery of Epigenetic Heredity, and Its Possible Impact on Longevity

The basic mechanisms of life and inheritance function much the same in worms, fruit flies, mice, and humans. That is one reason why lower life forms are used so often in longevity research. Much shorter lifespans is another reason. A recent Stanford study on worms provides a hint at an epigenetic method of inheritance which may eventually prove useful for extending lifespans in human offspring.

The study used Caenorhabditis elegans worms with very low levels of the SET-2 enzyme. The SET-2 enzyme normally adds methyl molecules onto DNA's protein packaging material. In doing so, the enzyme opens up the packaging material, allowing the genes to be copied and expressed. Some of those genes appear to be pro-aging genes, says Brunet. Her team knocked out SET-2 by removing genes that code for it. This had the effect of significantly lengthening the worms' lifespan, presumably because those pro-aging genes were no longer expressed.

Next, the long-lived, enzyme-lacking worms mated with normal worms. The offspring had the regular genes for making SET-2, and even expressed normal amounts of the enzyme, but they lived significantly longer than control worms whose parents both had regular lifespans. The life-extending effect carried over into the third generation, but returned to normal by the fourth generation (in the great-grandchildren of the original mutant worms). For the first few generations, having a long-lived ancestor increased life expectancy from 20 days to 25, extending a worm's life by 25 to 30 percent on average.

Brunet and her team haven't yet determined the exact mechanism for the lifetime extension, or which molecules are at work. This is one of the study's imperfections, says David Katz, who researches epigenetic transcriptional memory at Emory University. Regardless, "the effect is clearly epigenetic," he says, "and it's probably one of the most complicated traits that has been linked to epigenetic inheritance."

...The results, published October 19 in Nature (Scientific American is part of Nature Publishing Group), provide the first evidence that some aspects of lifespan length can be passed from parent to offspring, independent of the direct influence DNA. _SciAm

Contrary to what Dr. Katz asserts above, the fact that the research team hasn't determined the exact mechanism for the lifetime extension is one of the study's great promises.

Remember, it is often the questions that a study raises which causes the study to become frequently cited, and immortalised -- not necessarily the questions the study answers. Studies that raise good questions often act as springboards for entire new developments in science. Such may be the case here.