In order to reactivate silenced genes, a cell needs to remove certain “off” markers called methyl groups from the DNA. Scientists have recently shown that this process involves an intermediate step and an enzyme that also plays a role in the development of blood cancer. The finding could lead to new ideas for cancer-fighting therapies. Image: dkfz.de |
In
order to reactivate silenced genes, a cell needs to remove certain
“off” markers called methyl groups from the DNA. Scientists working with
Frank Lyko and Achim Breiling of the German Cancer Research Center
(Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg have shown that
this process involves an intermediate step and an enzyme that also plays
a role in the development of blood cancer. The researchers have now
reported their findings in Nature Communications.
When
a stem cell develops into a specific cell type, genes are turned on and
then off again in a predetermined order. This is accomplished by
epigenetic programming. The programming language frequently used by the
cell consists of chemical markers called methyl groups. Attached to the
DNA, they turn off the respective genes. In order to reactivate silenced
genes, the methyl groups must be removed again.
“In
the lab, we can artificially induce stem cells to differentiate using
retinoic acid,” Achim Breiling explains. “We were interested in how the
chemical markers change in the process.” The scientists studied these
processes in a specific group of genes known as HOXA cluster. In an
undifferentiated stem cell, this group of genes is silenced. However,
once the cell starts developing into a specific direction, such as into a
nerve cell or a blood cell, the genes are frequently activated in the
order in which they are arranged in the cell’s genetic material: one
after the other, from front to back.
The
investigators found that retinoic acid activated the HOXA genes in
order of appearance, as expected. At the same time, the methyl groups on
the DNA disappeared, and more hydroxymethyl groups were found.
Subsequently, all methyl groups in the active part of the gene cluster
were replaced by hydroxymethyl groups.
“The
methyl group is probably not directly removed, but first gets converted
into hydroxymethyl, as an intermediate step, so to speak, on the way to
an active gene,” Frank Lyko explains. This intermediate step is
accomplished by TET enzymes; they transfer the hydroxyl group. TET2, in
particular, appears to play an important role: Addition of retinoic acid
leads to a significant rise in the TET2 level. Frank Lyko explains:
“This brought us to the question of what happens if TET2 is no longer
present in the cells: Does this have an impact on differentiation?”
And
really, when the investigators turned off this enzyme in the stem
cells, activation of HOXA genes by retinoic acid was disrupted.
“Silencing TET2 seems to delay stem cell differentiation,” says Achim
Breiling.
These
findings might also be of interest for cancer research. Thus, patients
suffering from a type of blood cancer called myeloid leukemia often have
mutations in the TET2 gene. Their blood stem cells cannot develop into
white blood cells; precursor cells proliferate rapidly, and blood cancer
develops.
“Our
results may explain the connection of the TET2 gene mutation with the
development of cancer”, said Frank Lyko. “This may also hold potential
for new ideas for therapy.”
Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster
