Scientists Find Missing Link Between Players in the Epigenetic Code
Research has established the first link between the two most fundamental epigenetic tags histone modification and DNA methylation in humans
Over the last two decades, scientists have come
to understand that the genetic code held within DNA
represents only part of the blueprint of life.
The rest of that blueprint comes from specific patterns
of chemical tags that overlay the DNA structure,
determining how tightly the DNA is packaged and how
accessible certain genes are to be switched on or off.
As researchers have uncovered more and more of these "epigenetic" tags, they have begun to wonder how they are all connected. Now, research from the University of North Carolina School of Medicine has established the first link between the two most fundamental epigenetic tags histone modification and DNA methylation in humans.
The study implicates a protein called UHRF1
in the maintenance of these epigenetic tags.
Because the protein has been found to be defective
in cancer, the finding could help scientists understand
not only how microscopic chemical changes can
ultimately affect the epigenetic landscape,
but also give clues to the underlying
causes of disease and cancer.
The study was published Sept. 30, 2012 by the journal Nature Structural & Molecular Biology.
"There's always been the suspicion that regions marked by DNA methylation might be connected to other epigenetic tags like histone modifications, and that has even been shown to be true in model organisms like fungus and plants," said senior study author Brian Strahl, PhD, associate professor of biochemistry and biophysics in the UNC School of Medicine and a member of UNC Lineberger Comprehensive Cancer Center. "But no one has been able to make that leap in human cells. It's been controversial in terms of whether or not there's really a connection. We have shown there is."
Strahl, along with his postdoctoral fellow Scott Rothbart, honed in on this discovery by using a highly sophisticated technique developed in his lab known as next generation peptide arrays. First the Strahl lab generated specific types of histone modifications and dotted them on tiny glass slides called "arrays." They then used these "arrays" to see how histone modifications affected the docking of different proteins. One protein UHRF1 stood out because it bound a specific histone modification (lysine 9 methylation on histone H3) in cases where others could not.
Strahl and his colleagues focused the rest of their experiments on understanding the role of UHRF1 binding to this histone modification.
They found that while other proteins that dock
on this epigenetic tag are ejected during
the mitosis phase of the cell cycle,
UHRF1 sticks around.
Importantly, UHRF1's association with histones
throughout the cell cycle appears to be critical
to maintaining another epigenetic tag
called DNA methylation.
This result was surprising because researchers
had previously believed that the maintenance
of DNA methylation occurred exclusively
during a single step of the cell cycle
called DNA replication.
Strahl: "This role of UHRF1 outside of DNA replication is certainly unexpected, but I think it is just another way of making sure we don't lose information about our epigenetic landscape."
The research was funded by the National Institutes of Health and the North Carolina Biotechnology Center.
Study co-authors from UNC were Scott B. Rothbart, PhD, a postdoc in Strahl's lab at UNC; Krzysztof Krajewski, PhD, research assistant professor; and Jorge Y. Martinez, a former student in Strahl's lab.
Original article: http://www.eurekalert.org/pub_releases/2012-09/uonc-sfm092812.php