Scientists find missing link between players in the epigenetic code
Sept 30, 2012 | Live Science
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
The study, which was published Sept. 30, 2012 by the journal Nature
Structural & Molecular Biology, 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.
"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
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 a specific phase of the cell cycle, mitosis, UHRF1
sticks around. Importantly, the protein's association with histones
throughout the cell cycle appears to be critical to maintaining another
epigenetic tag called DNA methylation. The 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.
"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," said Strahl.
Journal reference: Nature Structural & Molecular Biology search and
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Provided by University of North Carolina Health Care