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Mouse ENCODE Collection Characterizes and Compares Regulatory Elements in Mice, Humans

NEW YORK (GenomeWeb) – Members of the Mouse ENCODE Consortium are sharing findings from their ongoing studies of gene regulation in the mouse model organism in a collection of papers published online today in Nature and Science.

The mouse effort is intended to augment information gleaned from the Encyclopedia of DNA Elements (ENCODE), a project undertaken more than a decade ago to untangle regulatory features in the human genome that influence gene expression and, consequently, cell function.

Another project known as modENCODE is applying similar strategies to untangle genetic regulation in the fruit fly, Drosphila melanogaster, and the Caenorhabditis elegans worm.

In one of four new Nature studies by Mouse ENCODE researchers, the Ludwig Institute for Cancer Research and University of California at San Diego's Bing Ren and colleagues introduced the project's purpose and progress.

"The assumption has long been that whatever was discovered in the mouse would likely be true in humans too, but the idea has never been systematically evaluated and assessed," Ren said in a statement.

So far, he and his co-authors noted, the Mouse ENCODE team has used RNA sequencing, DNase I hypersensitive site sequencing, chromatin immunoprecipitation-sequencing, and other analyses to track transcription patterns, replicating regions, transcription factor binding sites, chromatin marks, and other features in 123 mouse cell and/or primary tissue types.

The data reveals some of the same regulatory principles at play in mice as in humans, the study's authors reported, while also picking up particulars in these processes that are specific to each species.

Although many of the mouse sequences with apparent regulatory features appeared to be conserved between the mouse and human, for instance, details differed between the species when it came to gene expression and the features that regulated this process in various cell types, with some genes and regulatory features showing more pronounced divergence than others.

"There are a substantial number of mouse genes that are regulated in ways different from similar genes in humans," Ren said. "The differences are not random. They are clustered along certain pathways, such as in genes regulating the immune system."

"[A] lot of the genes are identical between a mouse and a human, but we would argue how they're regulated is quite different," co-corresponding author Michael Snyder, genetics chair at Stanford University, added in a statement. "We are interested in what makes a mouse a mouse and a human a human."

Earlier this week, Snyder and colleagues from Stanford, the Salk Institute for Biological Studies, and elsewhere published a study online in the Proceedings of the National Academy of Sciences that compared and contrasted transcriptional profiles in more than a dozen mouse and human tissues.

Members of that team also contributed to a second Nature paper looking at the binding patterns for nearly three dozen different transcription factors in the mouse genome. Again, the researchers found that the "general principles are the same in mice and people, but the details are quite different," Snyder said.

For example, the team saw transcription factors turning up at slightly different sites when considering corresponding targets. Based on such results, authors of the study argued that investigators attempting to translate information from mouse studies into humans in the future may benefit from consulting data generated for the Mouse ENCODE study to determine whether they're dealing with a gene with regulatory features that are similar to or different from those found in the model animal.

"If you focus on a gene that is similar to humans, the result should be easier to transfer from mouse to human," co-first author Yong Cheng, a post-doctoral researcher at Stanford University, said in a statement. "But if you're working on a gene that is different, you need to pay more attention to whether this result can be successfully applied to the human subjects."

Still other Nature studies mapped replication domains in the mouse cell and outlined circuits of regulatory elements acting near to and far from target genes in 25 mouse cell or tissue types.

Meanwhile, a study published online today in Science delved into cis-regulatory elements — those near the genes they influence — in greater depth using information at more than a million DNase I hypersensitive sites in the mouse genome. 

"Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each [transcription factor] has been strictly conserved," the University of Washington's John Stamatoyannopoulos and his co-authors wrote in Science.

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