Munich: Researchers have monitored how
epigenetic information is transmitted to daughter cells during cell
division and determined when the cell’s developmental memory is
re-established. Every cell in the body starts out with the same
complement of DNA and is equipped with all of the genetic information
present in the nucleus of the fertilized egg. The diverse cell types
that make up multicellular organisms differ in their structure and
function because each makes use of only a subset of the information
encoded in the nuclear genome. Proteins called histones serve as
scaffolds for the packaging of nuclear DNA molecules into ‘chromatin’,
the nucleoprotein complexes that become visible as condensed chromosomes
prior to cell division.
However, histones also play an active role in
determining which subset of nuclear genes is expressed in each
differentiated cell type. This differential packaging involves the
chemical modification of histones by the attachment of methyl (CH3) or
acetyl (CH3COO-) at specific target sites. These modifications in turn
regulate the accessibility of stretches of the chromosomal DNA to the
enzymes required for gene expression. Histone methylation often
represses gene expression, while acetylation activates it. A team of
researchers led by Professor Axel Imhof
at LMU‘s Adolf Butenandt Institute has now tackled the question of how
the pattern of histone modification present in a cell is passed onto its
daughter cells during cell division. The team reports the results of
the study in the journal “Genes & Development”.
To ensure that daughter cells express the same genetic program as
their progenitors, newly synthesized histones must be modified in
precisely the same way as those present in the mother cell prior to cell
division. “In order to comprehend how cancers originate, we have to
understand this mechanism of cellular memory, but so far little is known
about how it operates,” says Imhof. The LMU researchers used chemical
precursors containing heavy isotopes to label the new histones deposited
on specific stretches of the genomic DNA, enabling them to be
distinguished from the parental histones by means of mass spectroscopy.
In this way, the team was able to determine how and when during the cell
cycle the new histones acquired the set of modifications present in
their parental counterparts, and thus determine when the cell’s
epigenetic memory is re-established.
Loss of cellular memory
Imhof and his colleagues discovered that adding the correct
epigenetic marks to newly synthesized histones involves a race against
time. Most parental modifications are successfully re-established in the
course of a single cell cycle. “But there are cases in which parental
modifications are not faithfully transmitted,” says Imhof. In fact, this
happens whenever the next cell cycle is initiated before the modifying
enzymes reach the sites concerned.”
This result has important implications for tumor research. “Failure
to transmit histone modifications plays an important role in the loss of
epigenetic information that could lead to a dedifferentiation that is
characteristic of tumors,” says Imhof. In effect, tumor cells no longer
‘remember’ the type of differentiated cell lineage to which they
previously belonged. As a result of this loss of cellular memory, they
divide in an unregulated fashion, and proliferate so fast that they can
invade and disrupt neighboring tissues, endangering the survival of the
organism.
Reconfiguration of cellular memory
Conversely, embryonic stem cells possess the capacity to
differentiate into many different cell types, but they also divide very
rapidly. However, their ability to produce diverse cell types implies
that they can reconfigure (and selectively ‘forget’) the pre-existing
pattern of histone modifications in their chromosomes during cell
division. “In the ordered succession of cell differentiation that occurs
during normal embryonic development, changes in histone modification
play a very important role,” says Imhof.
Stem cell researchers are currently trying to understand the innate
flexibility of these cells, and exploit it for therapeutic purposes.
Thus it is possible to convert adult cells into pluripotent stem cells,
which can be persuaded to differentiate into various cell types. “The
problem is that the process is very inefficient,” Imhof remarks. He and
his colleagues now hope to identify inhibitors that block the action of
the enzymes responsible for histone modification, as such agents should
facilitate the targeted reprogramming of cells.