BERKELEY, CA -- The National Institutes of Health (NIH) today (May 14) announced the first grants in a four-year, $57 million effort to identify the functional elements in the genomes of the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans.
Researchers in the Life Sciences Division of the Department of Energy's Lawrence Berkeley National Laboratory are the principal investigators on two of the new grant projects, while other members of the division are co-principal investigators on additional projects. The projects are part of the ENCODE program (Encyclopedia of DNA Elements) administered by the National Human Genome Research Institute (NHGRI). The fly and nematode projects are dubbed modENCODE, because they are studies of model organisms.
Functional elements include DNA sequences for protein-coding and noncoding genes, regulatory elements in gene transcription, and those DNA sequences, along with proteins that bind DNA, that play a role in chromosome structure and dynamics. By understanding the functional elements in the genomes of flies and nematodes (round worms), NHGRI hopes to shed light on the workings of the human genome.
"I am delighted to see the leading roles that Berkeley Lab scientists are taking in this ambitious and important project," says Joe Gray, director of the Life Sciences Division and Associate Laboratory Director for Life and Environmental Sciences. "Understanding how genomes regulate transcription is essential to understanding numerous aspects of biology, ranging from normal organ development to the development of cancer. The model studies being initiated here in the ENCODE projects will provide important general information about how these genomes, both model and human, function."
Susan Celniker is principal investigator and Roger Hoskins is co-PI of a modENCODE grant project titled "Comprehensive Characterization of the Drosophila Transcriptome." The transcriptome, roughly speaking, means all the RNA products made in an organism under a specific set of circumstances, an indication of the genes and other DNA sequences that are actively transcribed under those conditions.
Says Celniker, "The unprecedented scope of our studies in Drosophila will provide the most comprehensive evidence of transcription both of genes that code for proteins and of noncoding DNA sequences for any organism. This knowledge is a prerequisite to understanding the control of gene expression."
Gary Karpen is PI of a grant project titled "Genome-wide Mapping of Chromosomal Proteins in Drosophila." Chromosomal proteins include the histones around which DNA wraps itself to form chromatin, plus many other proteins involved in the structure and regulation of chromosomes, such as DNA polymerases.
Says Karpen, "Our project is focused on determining the 'landscape' of Drosophila proteins associated with chromatin across the entire genome. Combined with other data, this information will help our understanding of how DNA performs critical functions, including inheritance and gene expression."
Research on the nematode C. elegans is represented by a modENCODE project for which Abby Dernburg is co-PI. Titled "Identification of DNA Elements Governing Chromatin Function in C. elegans," the project involves researchers from eight institutions in four countries and is led by principal investigator Jason Lieb of the University of North Carolina.
"Our data will provide insights into longstanding questions about developmental regulation of gene expression, differences between chromatin organization in somatic and germline cells, the three-dimensional architecture of the chromosomes within the nucleus, and the molecular mechanisms that enable chromosomes to replicate and segregate during cell division," Dernburg says.
Suzanna Lewis will collaborate on compiling and tracking all the data generated by the entire project under a modENCODE grant for "A Data Coordination Center for the Model Organism ENCODE project," led by Lincoln Stein of Cold Spring Harbor Laboratory, with Lewis, Gos Micklem of Cambridge University, and Jim Kent of UC Santa Cruz as co-PIs.
"At Berkeley we're at the receiving end," says Lewis, "and we'll be doing all the quality control and loading of the data."
As the data-coordination proposal explains, the modENCODE project is an important part of the human ENCODE effort because functional elements in the human genome can only be studied in cultured cells, which limits understanding of complex integrative processes such as cell-cell communication. By contrast, nonhuman model organisms can be manipulated in vivo -- for example by deleting functional elements from their genomes, modifying them, causing them to be overexpressed, or activating them in unusual contexts. These alterations may reveal the biological significance of the functional element.
"We are making great strides in identifying functional elements in the human genome, but we still don't know much about their biological relevance," says Francis Collins, director of NHGRI, noting that information about the "functional landscape" of D. melanogaster and C. elegans "should aid our efforts to tackle such questions in humans."
Elise Feingold, NHGRI program director in charge of the ENCODE and modENCODE projects, emphasizes the importance of comparing the genomes of model organisms to those of humans. "If a DNA sequence has been conserved throughout evolution -- from worm to fly to human -- it is very likely that the sequence is functionally relevant."
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