Photo: Michael Stallcup, Ph.D.
Researchers at the
Keck
School of Medicine of the University of Southern California (
USC)
have discovered key processes by which estrogen, the female sex
hormone, activates genes in breast-cancer cells. Greater understanding
of how this occurs is expected to eventually lead to new treatments for
the disease.
Michael R.
Stallcup, Ph.D., professor and chair of the Keck School’s
Department
of Biochemistry and Molecular Biology,
was the senior author, and Kwang Won Jeong, Ph.D., a postdoctoral
student in Stallcup’s lab, was the first author of the paper, “Recognition
of enhancer element-specific histone methylation by TIP60 in
transcriptional activation.” It was published online in the
research journal
Nature Structural
& Molecular Biology on Nov. 13.
The researchers found that a protein, TIP60, recognizes when a common
chemical process called methylation occurs in chromatin, the material
that enfolds all genes. Methylation controls how genes are folded in
the complex structure of chromatin, which determines whether the genes
are active or inactive. The researchers discovered that after
recognizing the methylation signal, TIP60 then binds to the signal,
connecting TIP60 to the chromatin and then changing the chromatin’s
structure, which helps to activate the gene. The methylation that TIP60
recognizes is generated by another protein, MLL1.
“It’s like when you’re in your car and come to a red light,” said
Stallcup. “The light doesn’t make you stop, but it is a signal that you
have to interpret and then decide to stop. In this case, the
methylation modification that TIP60 recognizes is one of those signals,
and then TIP60 acts on that signal.”
The findings build upon previous work of Stallcup’s lab. Earlier
published research revealed that the methylation of chromatin and other
proteins plays many important roles in controlling the activities of
genes.
While the recent findings are significant, Stallcup stressed that there
is much more to be discovered.
“We want to understand more about other steps in the process of gene
activation,” Stallcup said. “In particular, we’re interested in the
function of the MLL1 protein because we think it plays a key role in
controlling chromatin structure and folding, which we think is critical
for activation of genes by estrogen.”
Stallcup also noted that estrogen regulates just a few hundred of the
tens of thousands of genes in every human cell, but that the research
has broader implications.
“While the process we’re studying is the regulation of gene activity by
estrogen, the findings have potentially global significance,,because
the methylation modification of chromatin that TIP60 recognizes is
found in all active and potentially active genes in human cells,”
Stallcup said.