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modENCODE Teams Report on Functional Features of Fruit Fly, Roundworm Genomes

By Andrea Anderson

NEW YORK (GenomeWeb News) – In a series of papers appearing online in Science and Nature today, members of the "model organism Encyclopedia of DNA Elements," or modENCODE, Consortium reported on their efforts to characterize regulatory patterns in the genomes of two commonly used model organisms: the fruit fly, Drosophila melanogaster, and roundworm, Caenorhabditis elegans.

"Fruit fly and nematode modENCODE projects have performed hundreds of experiments and produced billions of data points to permit the building of new models of gene expression and regulation," University of Edinburgh evolutionary biology researcher Mark Blaxter wrote in an accompanying perspectives paper in Science.

"[T]he modENCODE and ENCODE deep genomics programs will, in time, deliver the power to model and predict organism function from multidimensional data, shine light on the dark genome, and hopefully allow a better understanding of the healthy human and how to treat human disease," Blaxter argued.

In the first of two Science papers, an international research team describes a set of experiments that they did to gain a more refined view of the C. elegans genome — including transcriptome studies done at different stages of development as well as experiments assessing transcription factor and chromatin patterns across the genome.

Together, such experiments helped the team to get "greatly refined gene models" for C. elegans, senior author Robert Waterston, chair of the University of Washington's department of genome sciences, told GenomeWeb Daily News.

And, he added, the researchers uncovered multiple transcription factor binding sites across the genome. Among them: so-called high occupancy target, or HOT, spots — transcription factor-rich areas resembling those also detected by researchers analyzing the Drosophila genome.

"Since we sequenced the genome [of C. elegans] more than 10 years ago we've been wanting to be able to read it better," Waterston said, noting that many protein coding sequences were just predictions that had not been experimentally verified prior to the new study.

Moreover, Waterston said, knowledge of chromatin and transcription factor binding sites in the genome was "meager at best."

He and his team used RNA-Seq to find previously unrecognized protein coding genes and alternative splicing events in the worm's genome — and to modify existing transcript information.

In addition, by finding and bringing together chromatin profiles, gene expression data, and refined gene models, Waterston explained, the team was able to associate specific histone marks with specific genes, gene activity patterns, parts of genes, and so on.

Despite the wealth of new information on the C. elegans genome, though, Waterston explained, there are still many experiments to be done, including transcriptome studies on additional cell and tissue types and more non-coding RNA studies.

The researchers eventually hope to look at the shared features found in the fly and worm genomes and compare those to those detected by members of the ENCODE project who are studying human cells.

"What we'd really like to do in the next year is to compare the [Drosophila and C. elegans] results in detail to find out what's common and then to take those things and look in humans to see how many of these features that we find in flies and worms can be applied to humans," Waterston said.

In a second Science paper, meanwhile, modENCODE team members provide an integrative view of their D. melanogaster studies, putting together information from hundreds of data sets generated through ChIP-chip, ChIP-seq, RNA-seq, and other fruit fly experiments.

"We have generated more than 700 data sets and discovered protein-coding, non-coding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome," the researchers wrote.

"Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene expression prediction," they added. "Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation."

A pair of Nature papers — also appearing online today — offer even more detail about some of the D. melanogaster experiments.

Lawrence Livermore National Laboratory Life Sciences Director Gary Karpen and his team brought together information on histone modifications, gene and promoter activity, Polycomb repressive protein patterns, and more as they mapped chromatin patterns in D. melanogaster embryo and larval central nervous system cell lines.

"This project was really conceived as an effort to generate high quality data for the community," co-corresponding author Peter Park, a biomedical informatics researcher at Harvard University who led the analysis arm of the study, told GWDN.

Together, findings from their ChIP-chip, ChIP-Seq, global run-on-sequencing, DNase I hypersensitivity, and other experiments suggest certain histone combinations and regulatory features tend to overlap in the fruit fly genome, consistent with the notion that "specific histone modifications work together to achieve distinct chromatin 'states.'"

When they looked at the various histone combinations in the genome, the team found distinct chromatin marks depending on the transcriptional activity of genes, but also within active genes. Their findings also highlight how chromatin patterns vary with gene structure and genomic context.

For instance, Park explained, the researchers uncovered a chromatin mark that frequently turns up in parts of the genome containing enhancer-like sequences that may regulate the activity other genes.

Such epigenetic annotation of the fruit fly genome represents "another layer of information that needs to be considered when we study DNA sequences," Park said, noting that such analyses are providing a more comprehensive view of the Drosophila genome.

Finally, senior author Susan Celniker, head of the US Department of Energy Lawrence Berkeley National Laboratory's genome dynamics department, and her colleagues used RNA-sequencing, complementary DNA sequencing, and tiling arrays to characterize the transcriptional profiles in 30 Drosophila developmental stages. In the process, they uncovered more than 110,000 new elements in the fruit fly genome — from new coding and non-coding genes to previously unrecognized splicing and editing events.

"Identification of thousands of new gene transcripts has significantly increased our knowledge of the protein repertoire used in fruit flies," Celniker said in a statement. "Our work provides new resources for studying development, sex determination and aging."

A set of modENCODE companion papers providing more information on chromatin, heterochromatin, and other patterns in the fruit fly genome are reportedly set to appear in an upcoming issue of Genome Research.

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