Dynamic Changes in Methylation Can Determine
Cell Fate Wednesday, 28 September 2011
Scientists at Cold Spring Harbor Laboratory (CSHL) and the
University of Southern California (USC) have uncovered intriguing new evidence
helping to explain one of the ways in which a stem cell's fate can be
determined.
The new data show how the "marking" of DNA sequences by
groups of methyl molecules – a process called methylation – can influence the
type of cell a stem cell will become. The cellular maturation process, called
differentiation, has long been thought to be affected by methylation. Subtle
changes in methylation patterns within subsets of a particular cell type have
now been observed and closely scrutinized, and they reveal some intriguing mechanisms
at work in the process.
A team led by postdoc Dr. Emily Hodges,
working in the laboratory of CSHL Professor and HHMI Investigator Gregory Hannon,
studied how methylation changes in blood stem cells can affect whether a given
stem cell will differentiate into either a myeloid cell or a lymphoid cell.
These are the two major lineages of mature blood cells. Sophisticated
mathematical analyses of the data were performed under the direction of USC
Professor Andrew D. Smith.
The study, which will appear in print
October 7 in the journal Molecular Cell, generated some surprising findings
that challenge currently held theories about how methylation operates. First,
it demonstrated that methylation patterns are more dynamic than they are often
thought to be.
"It's
not a question of methylation being 'on' or 'off' at a given site in the
genome," explains Hodges.
"We
find, instead, an interesting fluctuation of the boundaries of regions that are
free of methylation marks. This fact, in turn, can have a profound impact upon
cell fate."
Areas lacking methylation, called
hypomethylated regions, or HMRs, tend to coincide with so-called CpG islands,
sites in the genome where adjacent "Cs"
and "G's" – cytosine and
guanine nucleotides – are seen in strings of repeats. These unmethylated
regions tend to be ones associated with nearby genes that are capable of being
expressed. In contrast, sites in the genome that are methylated are typically
not expressed.
The new study, which looks at these
areas at high resolution in cells of the different blood cell lineages and in
blood stem cells, finds that in many cases, a core portion of the unmethylated
region is shared in common, but that adjacent areas, sometimes called "CpG shores" – the outlying
areas around CpG islands – differ markedly in breadth. The CSHL-USC team
refines the notion of islands and shores, preferring to describe the narrowing
and widening of the "shoreline"
as a tidal phenomenon.
"We
observed that the boundaries of these unmethylated regions goes in and out,
like the tides," says Hodges.
"The
key question is what drives these changes. We found that the width of these
regions depends on the gene that is associated with the region. We showed in
blood cells that the variation is lineage-specific."
The team deduced this after making
close study of the methylation patterns in genomic regions containing genes
known from other research to be expressed specifically in lymphoid cells, but
not in myeloid cells, or vice versa. In these cases, all blood cells share a narrow
"core" region of
hypomethylation; but only in one lineage did the unmethylated region widen – a
widening that opens the promoter of the "underlying"
gene to the cellular machinery initiating gene expression. In other words, the
lack of methylation over a wider area enables the underlying gene to be
activated – only in the specified cell-type, but not in any of the others.
Another striking observation made from
this data is the directional preference of this expansion. For example, in the
widening of the unmethylated region seen in the case of the lymphoid cell, the
direction of the widening was toward the area occupied by the underlying gene,
which in this case was a gene encoding a B cell surface marker called CD22.
It has generally been thought that methylation
is a stable epigenetic mark and that change in methylation are unidirectional;
and further, that cells become increasingly methylated as they move through the
differentiation process toward their mature identity. And in fact, the only
known direction of active change is from an unmethylated state to a methylated
state.
The new data suggests, however, that
dynamic changes in methylation status may be possible. The relevant evidence
comes from blood stem cells, which were observed to have methylation patterns
that the team describes as "intermediately
methylated," seemingly in dynamic equilibrium of the two extreme
states of "methylated" and "unmethylated."
According to Hodges, this raises the
possibility that methylation might in fact be bidirectional, and that there
might be an as yet undiscovered, active mechanism that performs de-methylation.
No known enzyme has this ability to remove methyl groups from DNA; DNA
methyltransferase is the well-known enzyme that catalyzes the addition of
methyl groups.
Yet another of the team's unexpected
findings concerns the position of HMRs relative to know genic regions. While
unmethylated regions tend to be associated with nearby genes that are capable
of being expressed, the team found, according to Hodges, "a lot of HMRs located far away from any annotated gene
locus."
One notable thing about these regions,
she says, "is that they were highly
enriched for binding sites of specific regulatory molecules that are involved
in chromatin organization."
Chromatin consists of DNA and the
protein complexes called histones around which genomic DNA is packed. In a
given cell, chromatin organization, like methylation, helps to determine
whether specific genes can be expressed or not.
About CSHL
Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped
contemporary biomedical research and education with programs in cancer,
neuroscience, plant biology and quantitative biology. CSHL is ranked number one
in the world by Thomson Reuters for impact of its research in molecular biology
and genetics. The Laboratory has been home to eight Nobel Prize winners. Today,
CSHL's multidisciplinary scientific community is more than 400 scientists
strong and its Meetings & Courses program hosts more than 8,000 scientists
from around the world each year. Tens of thousands more benefit from the
research, reviews, and ideas published in journals and books distributed
internationally by CSHL Press. The Laboratory's education arm also includes a
graduate school and programs for undergraduates as well as middle and high
school students and teachers. CSHL is a private, not-for-profit institution on
the north shore of Long Island.
Source: Cold Spring Harbor Laboratory
Contact: Peter
Tarr
Reference:
Directional DNA Methylation Changes
and Complex Intermediate States Accompany Lineage Specificity in the Adult
Hematopoietic Compartment Emily Hodges, Antoine Molaro, Camila O. Dos Santos, Pramod Thekkat, Qiang Song, Philip J. Uren, Jin Park, Jason Butler, Shahin Rafii, W. Richard McCombie, Andrew D. Smith and Gregory J. Hannon
Molecular Cell October 7, 2011, doi:10.1016/j.molcel.2011.08.026
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