Researchers find evidence of
second genetic code
and mapping the human genome was the first essential step for
scientists to study where genes for diseases such as cancer are
located. But in studies to identify the complex factors that make
those genes active or inactive, molecular genetic researchers
at the University have discovered a new area outside the DNA itself
that may show existence of another type of genetic code.
four articles published in the Aug. 10 issue of the journal Science,
U.Va. researchers and collaborators at the National Institutes
of Health (NIH) and Cold Spring Harbor Laboratory in New York,
as well as the Research Institute of Molecular Pathology at the
Vienna Biocenter in Austria, describe how proteins called histones,
around which the DNA is coiled, form a structure called chromatin
and provide sites where additional gene regulation appears to
occur, acting, in effect, as a master on/off switch.
David Allis, U.Va. Byrd Professor of Biochemistry and Molecular
Genetics, explains that the scientific community has known for
some time that the location of specific genes within chromatin
appears to determine whether that gene is on or off.
The DNA in our cells is not naked, and as a consequence
of its form in chromatin, it makes a difference in what kind of
chromatin neighborhood a particular gene finds itself.
a gene is located in a bad neighborhood, so to speak,
it will likely become silenced, and if that gene is a cancer-preventing
gene, this change in expression may cause disease, Allis
said. If the same gene is located in a good chromatin
neighborhood where its turned on, then the disease is less
likely to be expressed.
a gene that may cause the development of a disease like cancer
may be located in an area of the chromatin where its switched
off, and therefore this may be effective for stopping the disease.
The most remarkable part is that some changes in expression occur
without any changes in the DNA itself, which simply carries our
genetic information waiting to be expressed. Our research is attempting
to understand what we have referred to as a histone code
how chemical changes affecting the histone proteins affect
gene expression and could eventually lead to the development
of highly targeted and highly effective therapies for disease
control through gene regulation.
Science papers describe a process called methylation, wherein
a chemical methyl group is added to histones. The studies suggest
that exactly where the methylation mark appears in the histone
proteins makes a big difference.
these studies suggest that methylation of histones can act like
a master on/off switch that is indexing our genome
in ways that we have only begun to appreciate, according to Allis.
cell is somehow making choices about using histone methylation
to turn a gene on or off, said Allis, who co-authored several
of the research articles along with a review on this topic with
Thomas Jenuwein of the Vienna Biocenter. We believe that
what is telling the cell to make those choices is an overall code
that may significantly extend the information potential of the
genetic DNA code itself.
some time, we have known that there is more to our genetic blueprint
than DNA itself. We are excited that we are beginning to
decipher a new code, what is referred to as an epigenetic histone
their article, Translating the Histone Code, the authors
discuss how such a code is translated into biological functions.
we know how to control which genes we want to turn on or off,
we might be able to reduce disease risk, Allis said. For
example, we could turn off genes that promote tumor growth to
help prevent cancer development, and turn on other genes that
has co-authored several studies that show evidence that histone
methylation is at the heart of this common on/off switch. In a
second article in todays issue of Science, Allis and two
scientists at Cold Spring Harbor Laboratory, show that the on-off
system works with large blocks of chromatin in yeast. A group
at NIH has obtained similar data supporting these conclusions
using the expression of blood-forming genes in the chicken for
experiments suggest that the same system is at work in human cells
where it seems to control gene expression phenomena that include
X inactivation and imprinting, processes where whole chromosomes
or domains within chromosomes are selectively turned off during
these data indicate that this switch or indexing system for our
genome is most fundamental, existing in even the simplest genetic
organisms like yeast, and has not changed dramatically with mammalian
evolution, Allis said. The link between histone methylation
and defects in human imprinting demonstrate clearly that human
disease is tied to mistakes made in this marking system.
evidence is beginning to link alterations in chromatin structure
to cell cycle progression, DNA replication, DNA damage and its
repair, recombination and overall chromosome stability,
Allis said. If this histone code hypothesis is correct and
an on/off master switch exists for genes that are housed in chromatin,
the implications for human biology and disease, including cancer,
stem cell biology and aging, are far-reaching.