Gene regulation splits mice and men

"At the end of the day, a lot of the genes are identical between a mouse and a human, but we would argue how they're regulated is quite different," explains Michael Snyder. (Credit: iStockphoto)

The lab mouse has long been considered one of the best models for researching disease in humans, thanks to the genetic similarity between the two mammals.

Now, researchers have found that the basic principles of how genes are controlled are similar in the two species, which validates the mouse’s utility in clinical research.

However, there are important differences in the details of gene regulation that distinguish us as a species.

“At the end of the day, a lot of the genes are identical between a mouse and a human, but we would argue how they’re regulated is quite different,” says Michael Snyder, professor and chair of genetics at Stanford University. He is co-senior author of the main paper in Nature that describes the overall findings of the project, and of two companion papers.

“We are interested in what makes a mouse a mouse and a human a human.”

Gene regulation and gene expression

The research effort, Mouse ENCODE, is meant to complement a project called the Encyclopedia of DNA Elements, or ENCODE, that began in 2003.

ENCODE studied specific components in the human genome that guide genes to code for proteins that carry out a cell’s function, a process known as gene expression.

[related]

Surrounding the protein-coding genes are noncoding regulatory elements, molecules that regulate gene expression by attaching proteins, called transcription factors, to specific regions of DNA.

“We didn’t know before these research results that there are a large number of genes with expression levels systematically different between mouse and human,” says Ross Hardison, the director of the Huck Institute for Comparative Genomics and Bioinformatics at Penn State and senior corresponding author or co-senior author for four of the five new papers.

“Now we also know which genes have expression patterns that are shared between mouse and humans,” Hardison says. “For biological processes using genes with conserved expression patterns, the mouse is an excellent model for certain aspects of human biology.”

Why mice matter

Mouse ENCODE analyzed more than 100 mouse cell types and tissues to annotate the regulatory elements of the mouse genome and compare them to the regulatory elements in the human genome.

Because mice are used as model organisms for many human clinical studies and drug discovery, understanding the similarities and differences can help researchers understand how the results found in mouse studies can translate to humans.

“The mindset is when you compare things, it helps understand genome annotation,” says Mark Gerstein of Yale University, who collaborated on previous ENCODE research but is not part of the Mouse ENCODE consortium.

“It’s making the mouse a more meaningful model organism,” says Gerstein.

“At the end of the day, a lot of the genes are identical between a mouse and a human, but we would argue how they’re regulated is quite different,” explains Snyder.

Differences in the details

“Transcription factors are kind of like people: they work together in many different combinations to execute certain tasks,” says Snyder. “What we discovered is that the general principles are the same in mice and people, but the details are quite different. In general, the mouse factors are binding at different locations than the human ones in terms of the exact gene targets.”

“The mouse is the premier organism for modeling human disease and many other things—a lot of what we know about human biology does come from the mouse,” Snyder adds.

“The genome is what controls everything at some level. We’re interested in trying to understand the basic processes about how they’re similar or different across some of the most important species people are studying. It’s just fundamentally important.”

Sharing the wealth

More than a dozen companion studies have appeared or will appear in journals, including Nature, Nature Communications, Proceedings of the National Academy of SciencesGenome Research, and Genome Biology. ENCODE data are freely shared with the biomedical community, and the mouse resource has already been used by researchers outside of ENCODE in about 50 publications.

ENCODE was started with funds from the American Recovery and Reinvestment Act of 2009 and now is supported by the National Human Genome Research Institute (NHGRI), part of National Institutes of Health.

“The mouse has long been a mainstay of biological research models,” says NHGRI Director Eric Green. “These results provide a wealth of information about how the mouse genome works, and a foundation on which scientists can build to further understand both mouse and human biology. The collection of Mouse ENCODE data is a tremendously useful resource for the research community.”

Sources: Stanford, Penn State