Scientists often study mice as a model for human
biology and disease, because their basic biological processes are
assumed to be essentially the same as those of humans.
But now, a team of MIT researchers has uncovered a surprising
difference. In a study of gene regulation in mouse and human liver
cells, they found that master regulatory proteins function in very
different ways in mice and humans.
"Evolution has discovered several different ways to make a liver from
the same building blocks," said Ernest Fraenkel, MIT assistant
professor of biological engineering and leader of the research team.
"Comparing these different ways of regulating genes may unlock some
of nature's most closely guarded secrets."
The work, which will be published in the May 21 online edition of
Nature Genetics, could help identify patterns in the extremely
complicated control mechanisms involved in gene expression.
"You can think of it as two different dialects of the same language.
By exploring the human and mouse versions, we hope to find an
underlying grammar," said Fraenkel.
Every cell in the human (or mouse) body has the same collection of
genes, but the genome of each cell is carefully regulated so that
only certain genes are expressed. Regulatory proteins known as
transcription factors control this expression by binding to specific
locations within the genome and turning nearby genes on or off.
The researchers and their colleagues had previously worked out many
aspects of gene regulation in the human liver, which is one reason
the researchers chose to study the liver. In the current study they
compared 4,000 human genes with nearly identical counterparts, known
as homologous genes, from mouse liver cells.
Given the similarity between the two species' DNA sequences, the
researchers expected that transcription factors would bind to the
same sites in most pairs of homologous genes. To their surprise, they
found that most of the binding sites-between 41 percent and 89
percent, depending on the transcription factor-were in different
locations in humans and mice.
"The number of genes with the identical regulation in both species
was very, very small," Fraenkel said.
Before they began, the researchers expected to see some differences
in gene regulation between mice and humans, because the human liver
has evolved to process cooked food, said Fraenkel. However, the
magnitude of change was much higher than they anticipated.
Fraenkel speculated that the changes accumulated without having much
of an effect on gene expression. Unless the location of binding sites
affects gene expression, it is not under any natural selection
pressure.
All of that meaningless variation makes it harder to identify the
small number of genes where binding site migrations do have an
evolutionary impact, because they are being drowned out by all the
insignificant changes, Fraenkel said. In future studies, the research
team plans to investigate why some genes' binding sites are conserved
over time while others shift.
"We want to understand what's special about those genes," Fraenkel said.
Fraenkel said the results should provide guidance for researchers who
study mice to better understand human biology. "To get the most out
of mice for biomedical research we need to fully map out the
regulation in both organisms," he said.
Lead authors on the paper are Duncan Odom, a former postdoctoral
associate at the Whitehead Institute for Biomedical Research now at
Cancer Research UK, and Robin Dowell, a postdoctoral fellow in MIT's
Computer Science and Artificial Intelligence Laboratory.
Other authors are Elizabeth Jacobsen and Caitlin Conboy, technical
assistants at the Whitehead Institute; William Gordon, a technical
assistant in the Department of Biological Engineering; Timothy
Danford, Kenzie MacIsaac and Alexander Rolfe, graduate students in
electrical engineering and computer science; and David Gifford,
professor of electrical engineering and computer science.
The research was funded by the National Institutes of Health, Cancer
Research UK and the Whitaker Foundation.
Anne Trafton, MIT News Office
www.mit.edu