By manipulating the DNA of fruit flies and analyzing their body types
as they develop � as maggots � the team made a surprising finding: The
cancer-promoting effects of a mutation to the DNA sequence of a gene
that normally suppresses cancer can be passed from parents to
offspring, even if the mutation itself is not passed to the offspring.
Under some circumstances, having one parent with the mutation is
enough to ultimately affect the offspring, even when the mutation
itself is not passed to the next generation.
The work offers a stark illustration of a reality that scientists are
coming to fully respect only recently: Even though the DNA code has
been traditionally considered the only way to pass genetic information
through the generations, there are other, more subtle genetic legacies,
types of a �molecular memory� that can go from generation to
generation as well.
The team made the finding with a cancer-causing gene, or oncogene,
known as an activated JAK kinase. A biochemical system extremely
similar to JAK is vital for people�s health, but when its signals run
amok, the system can play a role in the development of leukemia or
lymphoma.
For decades, scientists have been teasing out DNA�s secrets, learning
how one snippet of DNA controls another, how some genes wield
incredible power over others, and how the DNA code encrypts all kinds
of biochemical signals � start, stop, turn on, turn off, and so on.
Scientists have made great progress understanding the complex signals
that govern diseases like cancer, often finding that a key gene that
should be on is turned off, or that a gene that is supposed to be off
is turned on, or that a mutant gene creates a faulty protein that
doesn�t work correctly.
Now researchers are trying to make more sense of the glut of genetic
information becoming available. For instance, what does a given
sequence of chemical bases that make up our DNA, such as
ACTGGGCTAGTTGGCAGT, really mean for our health" Scientists are turning
more attention to the big picture, looking at broad mechanisms that
determine how our bodies interpret the DNA, the master blueprint that
controls how an organism develops and functions. It�s part of a body
of work known as �epigenetics.� The main idea is that genetic
information can be regulated on a more global scale than just on a
gene-by-gene basis, which has been the focus of much genetic research
thus far.
The team, based in the University�s Department of Biomedical Genetics
and the James P. Wilmot Cancer Center, has shown how epigenetic
information can play a significant role in causing cancer.
�You might assume that a fruit fly that inherits a mutation that can
increase cancer is more at risk for the disease than its sibling that
does not inherit that mutation,� said geneticist Willis Li, Ph.D., the
lead author of the study and associate professor in the Department of
Biomedical Genetics.
�We have found an example where this is not true. We found that the
cancer-causing effects of certain mutations can persist in cells that
don�t even carry the damaged gene, and that these effects can be
passed from one generation to the next even though they�re not
actually in the DNA code. The mutation�s effects on the DNA of one of
its parents affect the genes of its offspring. Even though the
mutation is in one fly but not in another, both are affected equally,�
said Li.
To understand the work, it helps to think of large stretches of DNA,
sometimes encompassing many genes, as valuable parcels of information
that must be handled with precision and great care, not only as they
are passed from generation to generation but also during the lifespan
of an individual. Such packages contain little flags or markings. Just
as a regular package might have the words �handle with care� stamped
on it, our DNA has chemical signals that tell the body things like,
�Don�t turn this set of genes on� or �Turn these genes on only in case
of emergency.� No matter what�s �inside the package� � no matter the
specific DNA code � such chemical signals on the outside provide
instructions that help the body determine what to do with the DNA.
The instructions frequently come through a mechanism known as DNA
methylation, which the body uses often to turn genes off. Normally,
such chemical markings are wiped clean and reset very early in an
organism�s life through a process known as epigenetic reprogramming.
But Li�s team showed that JAK � specifically an activated JAK kinase
known as HOP-Tum-l � can disrupt that reprogramming, so that the
offspring inherit the methylation pattern of a parent. In other words,
the specific pattern of genes that are destined to be turned on or off
� the instructions for what to do with the DNA � is mistakenly passed
on from parent to offspring.
While scientists have known that epigenetic information can be passed
from generation to generation, Li says this is the first time the
phenomenon has been linked to a cancer-causing gene.
To do the study, Li�s team focused on the interaction between JAK and
a gene known as Kr�ppel, best known for playing a major role in the
development of a fruit fly�s body. It turns out that Kr�ppel also enhances an organism�s ability to suppress tumors, and if the normal
gene is knocked out or replaced by a faulty version, an organism is
more likely to develop cancer when another cancer-causing gene like
JAK is present.
His team found that some flies with a normal version of Kr�ppel got
just as many tumors as their brethren with the bad copy � about three
times as many tumors as most fruit flies with the normal version �
simply because one of their parents harbored the JAK oncogene.
Scientists believe the JAK mutation somehow messed up the �package�
that contained Kr�ppel, and this damage causes problems a generation
later, even when the faulty Kr�ppel gene is no longer around.
�In Jurassic Park, all the knowledge that was needed to re-create
dinosaurs was gotten out of ancient DNA embedded in amber,� said Dirk
Bohmann, Ph.D., a colleague and fellow fruit-fly researcher who was
not directly involved in the study. �Willis and other scientists are
showing that there is so much more that goes into controlling and
regulating genetic information than just knowledge of the DNA code.
Michael Crichton would have a harder time making that film today,
given what has been discovered in recent years.
�This work tells us that we have to pay more attention to the ways in
which DNA is packaged. It�s not just about the DNA sequence,� Bohmann
added.
Last year in a paper in Nature Genetics, Li first showed that JAK is a
more powerful oncogene than previously thought, with the ability to
turn on cancer-causing genes that are normally silent, through another
epigenetic mechanism involving gene packaging. The new work shows that
the gene is also able to suppress cancer-suppressing genes that are
normally turned on, making JAK even more of a threat than had been
known.
Work like Li�s is getting the attention of pharmaceutical companies,
which are developing drugs that target an organism�s DNA governance at
the epigenetic or �packaging� level. Such work provides a new target
for developing drugs to stop cancer, and it reminds scientists just
how much more research is necessary before we fully understand the
workings of ACTGGGCTAGTTGGCAGT and the countless other DNA sequences
in our body.
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