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Searching for the Genome's Second Code

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Searching for the Genome's Second Code G ENES IN ACTION NEWS ECTION S Searching for the Genome’s Second Code The genome has more than one code for specifying life. The hunt for the past 20 years. We have to change our way PECIAL various types of noncoding DNA that control gene expression is heating up of thinking.” S Molecular biologists may have sequenced time and in the right amount. From genes to regulation the human genome, but it’s going to take Most are tackling the functions of At the Medical Research Council’s Lab- molecular cryptographers to crack its com- regulatory elements one at a time, oratory of Molecular Biology in Cambridge, plex code. Genes, keystones to the devel- although a few are taking more global and U.K., Francis Crick—co-discoverer of opment and functioning of all organisms, bioinformatics approaches (see sidebar on DNA’s structure—Sydney Brenner, and their can’t by themselves explain what makes p. 635). At the California Institute of colleagues took the first steps toward cows cows and corn corn: The same genes Technology (Caltech) in Pasadena, one figuring out how genomes work. In 1966, have turned up in organisms as different group is trying to identify all the regulatory they proved that genes are written in a three- as, say, mice and jellyfish. Instead, new interactions in maturing embryos; their unit code, each of which specifies a particular findings from a variety of researchers have goal is to elucidate how genes and regulatory amino acid. By combining these threesomes, made clear that it’s the genome’s exquisite DNA work together to guide development called codons, in different ways, the genome control of each gene’s activity—and not and also how those interactions change encodes instructions for thousands of the genes per se—that matters most. over evolutionary time. proteins. This discovery focused the spot- “The evolution of the genetic diversity All this work is making clear that buried light on genes themselves and the coding of animal forms is really due to differences in DNA sequence is a regulatory code akin regions within them; for decades biologists in gene regulation,” says Michael Levine, an to the genetic code “but infinitely more called the intervening DNA “junk.” evolutionary biologist at the University of complicated,” says Michael Eisen, a Consequently, the notion of gene regula- California (UC), Berkeley. Turning on a computational biologist at Lawrence tion languished, even when results pointed gene at a different time, or in a new place, Berkeley National Laboratory in California. to its importance. In the early 1970s, Allan or under new circumstances can cause vari- Researchers can predict the proteins Wilson of UC Berkeley and his student, ations in, say, size, coloration, or behavior. specified by the genetic code, but, he adds, Mary Claire King, demonstrated that If the outcome of that new regulatory pat- “we can’t predict gene expression by humans and chimps are quite similar in tern improves an organism’s mating success simply looking at the sequence.” their genes. The key to what makes the two or ability to cope with harsh conditions, Manolis Dermitzakis of the Wellcome species so different, they suggested, lies in then it sets the stage for long-term changes Trust Sanger Institute in Cambridge, U.K., where and when those genes are active. and, possibly, the evolution of new species. agrees: “The complexity of the genome is But not until 2 years ago did experiments Unfortunately, “people don’t look to reg- much higher than we have defined for the begin to bear out this idea. Wolfgang Enard ulatory elements as the cause of the varia- of the Max Planck Institute for Evolutionary tion they see,” says Stephen Proulx of the Anthropology in Leipzig, Germany, and his University of Oregon, Eugene. These ele- colleagues compared the expression of ments are “a major part of the [evolution] many genes in tissues from chimps and story that’s been overlooked,” Levine says. humans. Certain genes are far more active in That neglect is now being righted. the human brain than in the chimp brain, Although many biologists remain gene- they reported in the 15 April 2002 issue of centric, an increasing Science (p. 340), a find- number are trying to fac- ing that supports Wilson tor in the effects of gene and King’s ideas. regulation. Researchers Enard’s 2002 work are beginning to come up came on the heels of with efficient ways to dozens of other studies SCIENCE locate the different regu- suggesting that gene latory regions scattered changes are not the be-all along the strands of and end-all of evolution- DNA. Others are piecing ary innovation. Instead, together the workings of researchers increasingly transcription factors, pro- attribute innovation to a teins that interact with variety of types of regula- regulatory DNA and with tory DNA, some just re- each other to guide gene cently detected. Certain activity. They are homing genes code for the pro- in on exactly where tran- teins that make up the scription factors operate transcription machinery, along the DNA and what Model organism. Fruit flies have played a critical role in the search for stretches of which binds to promot- they do to ensure that a regulatory DNA called enhancers, which control gene expression by binding to one or ers, the DNA right at the gene turns on at the right more transcription factors. beginning of a coding se- CREDITS (TOP): RESEARCHERS INC., PHOTO 2002; N. (BOTTOM) KEVITIYAGALA/ 632 22 OCTOBER 2004 VOL 306 SCIENCE www.sciencemag.org Published by AAAS G ENES IN ACTION S PECIAL Hot on the enhancer trail dozen of what seem to be complex enhancers; To understand the role of recently the count has more than doubled. enhancers in development, And in pinning down these enhancers, the Levine is studying their archi- researchers uncovered almost 50 genes that S tecture and function in the fruit seem to be controlled by this same set of tran- ECTION fly genome. The first challenge scription factors and thus are likely to work he encountered was simply together to guide early development finding the elusive quarry: So far, the researchers have confirmed Several years ago he encour- that at least some of these newly identified aged his graduate student clusters really are enhancers by testing their Michele Markstein (and her activity in transgenic fruit flies. They add computer-savvy parents) to DNA consisting of the putative enhancer write a computer program that and a marker gene. If the marker gene could begin to do just that. shows up in the same place as the The trio worked first with enhancer’s target gene, then the researchers a transcription factor, dorsal, know they have got what they want. These which was known to affect a data are showing that when several gene called zen. They already enhancers have a similar binding site knew that the enhancer for composition, they tend to work together and zen contained four binding coordinate the expression of sets of genes. Genome cryptography. The regulatory code is encoded in the sites for dorsal, packed close arrangement of an enhancer’s DNA binding sites (A), in the together. The researchers used Enhancer encryption spacing between binding sites (B), or by the loss or gain of one that signature sequence as With the first enhancers in hand, Levine and or more of these sites (C). a probe for finding other his colleagues were ready to take the next enhancers that also had step: to figure out how enhancers orches- quence. Other genes code for transcription clusters of dorsal binding sites. trate development and effect the changes factors that can be located anywhere in the The method worked. Proof positive came underlying evolution. They began to dissect genome. All affect their target genes by at- when the program pinpointed three previously the architecture of these bits of sequence, taching to regulatory DNA—sometimes identified enhancers that control other genes. determining exactly where the transcription called modules—that’s usually near but not It also turned up a dozen more clusters factor dorsal attached and whether those next to a gene. Protein-laden modules that containing three or four of dorsal’s binding locations had anything to do with the stimulate gene activity are called en- sites. The researchers have since shown that enhancer’s function. They also tracked down hancers; those that dampen activity are at least two are definitely enhancers. Levine transcription factors that interacted with the called silencers. is encouraged: “Sometimes the clustering of same enhancers as dorsal. As a plethora of meetings and research a single factor’s binding sites is sufficient to Through these efforts, Levine and UC reports suggests, enhancers are hot. They find new enhancers,” he says. Indeed, using a Berkeley collaborator Albert Erives have are small genetic command centers, similar strategy, Eisen identified a set of been able to decipher another layer of consisting of stretches of 500 or so bases. enhancers responsible for anterior-posterior “code” scattered in the arrangement of Those clusters in turn are peppered with development in the fruit fly. The groups binding sites within the enhancer. This code transcription factor binding sites, which published their results 2 years ago. can be less than 10 bases long. The target That same year, Eisen, Levine, of a particular enhancer—and its effect— and UC Berkeley’s Benjamin depends on the spacing and order of the Berman teamed up to use this binding sites within it. approach, along with other Sometimes the enhancer simply contains bioinformatics tools, to look for ; (BOX WITHIN) PHOTO RESEARCHERS INC.,;WITHIN) PHOTO (BOX 2002 multiple copies of the same binding site and more complex enhancers.
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