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ENCODE, modENCODE Data Reveal Conserved Regulatory Features Across Model Organisms, Humans

NEW YORK (GenomeWeb) – A set of studies published online today in Nature offers a look at similarities and differences detected in the regulatory machinery over time and across organisms.

By drawing on data generated through the ENCODE and modENCODE projects, members of those consortia considered the interplay between gene expression profiles, chromatin network arrangements, and other regulatory features in human, fruit fly, and Caenorhabditis elegans worm tissues — efforts that revealed extensive conservation for some aspects of the regulatory process.

In one of the studies, for instance, members of the ENCODE and modENCODE groups used RNA sequencing data generated from hundreds of worm, fruit fly, and human tissues samples to compare the sets of genes that are co-expressed during various stages of development in the three species.

Their results revealed comparable sets of coding genes and non-coding sequences — including genes known for their developmental roles — that tended to appear and disappear in unison in each of the organisms.

Moreover, the team determined that gene expression profiles in any of the three species could largely be predicted from a promoter chromatin state-based expression model developed using data from just one of the three organisms.

"It is remarkable to find these similarities across a half billion years," the study's co-first author Mark Gerstein, a computational biology and bioinformatics researcher at Yale University, said in a statement. "It also illustrates how studying model organisms can help us to annotate the human genome."

Together with researchers at Stanford University, the Massachusetts Institute of Technology, the University of Chicago, and elsewhere, Gerstein also co-authored a modENCODE paper that compared binding patterns for hundreds of transcription regulatory factors in the human, C. elegans, and Drosophila genomes.

From more than 1,000 datasets representing 165 transcriptional regulators in the human genome, 93 factors governing transcription in C. elegans, and 52 such factors in the fruit fly genome in various tissue types and developmental stages, that team observed the structure of the regulatory networks and their similarities across the three organisms.

Again, the analysis revealed a surprising degree of conservation, researchers reported, despite the long divergence times for the animal lineages considered and their obvious physical and developmental differences.

"We're trying to understand the basic principles that govern how genes are turned on and off," co-senior author Michael Snyder, genetics chair at Stanford University, said in a statement.

"The worm and the fly have been the premier model organisms in biology for decades, and have provided the foundation for much of what we've learned about human biology," he elaborated. "If we can learn how the rules of gene expression evolved over time, we can apply that knowledge to better understand human biology and disease."

Snyder and University of Washington researcher Robert Waterston also led a group that used chromatin immunoprecipitation sequencing to track binding by transcription factors, polymerase proteins, enhancers, and other regulatory proteins to the C. elegans genome over time in tissues collected at different stages of the worm's development.

Along with experiments designed to gauge the expression of transcription factor genes, the extensive ChIP-seq experiments helped the researchers place more than 90 transcription factors into their respective regulatory circuits, characterized by co-binding and co-expression patterns.

The team got a glimpse at the processes governed by such circuits as well. Using information on transcription factors targets with "high-occupancy" or "extreme occupancy" in developing embryos, for example, they defined some of the regulatory features that prompt cells to differentiate into appropriate C. elegans lineages and cell types.

Finally, researchers from centers around the world brought together hundreds of ChIP-seq and chromatin immunoprecipitation-plus-array datasets from ENCODE and modENCODE to delineate chromatin organization patterns along fruit fly, worm, and human chromosomes.

In that analysis, the study's authors highlighted some of the chromatin features conserved amongst the organisms, but also emphasized the inter-species differences they detected, including distinct distributions for repressive chromatin marks.