Robert Karl Stonjek
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 Posted: Fri Jul 11, 2008 4:34 pm Post subject: News: Scientists use genomic tools to create maps of DNA met |
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Scientists use genomic tools to create maps of DNA methylation
(PhysOrg.com) -- Much of the field of stem cell biology and development
remains uncharted territory. Just as famous explorers and astronomers mapped
out landmasses and constellations, researchers are working fervently to
chart the molecular landscapes within stem cells - especially embryonic stem
cells. A clearer understanding of the cells' unique properties, particularly
their ability to give rise to nearly any type of cell, could unlock
fundamental questions about biology and may even spur novel ways to treat
disease.
A team of researchers at the Broad Institute of Harvard and MIT has helped
break new ground in stem cell research through work described in two recent
Nature papers. The most recently published study, appearing in the July 6
advance online issue, involves an effort to map regions of cells' genomes
marked by DNA methylation - one of several so-called 'epigenetic'
modifications.
If DNA is the blueprint of a living organism, epigenetic marks, often in the
form of chemical tags called methyl groups, are the gatekeepers to that
blueprint. When affixed to DNA or to its protein scaffold (called
"chromatin"), methyl groups can enable genes to be switched on or off,
orchestrating signals that allow cells in the body, which share the same
DNA, to assume different forms and functions.
In work published last year, Broad Institute researchers applied genomic
tools to map the methylation of chromatin proteins called histones across
the genomes of several types of cells, including embryonic stem cells. To
complete that "epigenomic" picture, they decided to expand their work to
include DNA methylation. "We used some of the latest genomic technologies,"
said co-first author Alex Meissner, an assistant professor in Harvard>s new
Department of Stem Cell and Regenerative Biology, "to address a question
many have wondered about: what>s the role of DNA methylation in cell
development and differentiation?"
A long road towards DNA methylation maps
Researchers from the Whitehead Institute, Harvard University, and Harvard
Medical School came together at the Broad Institute to analyze DNA
methylation throughout the genomes of embryonic stem cells, as well as more
developmentally mature cells.
Meissner said the new DNA methylation maps are the result of a long-term
effort to address fundamental questions about how epigenetic factors
influence cell development.
Researchers are able to create these maps using a technique known as
bisulphite DNA sequencing. Although epigenetic information generally cannot
be read from the As, Gs, Cs, and Ts that make up the DNA code, it turns out
that a special chemical, sodium bisulphite, actually makes it possible to
detect epigenetic modifications. Just as fine powders help detectives
identify otherwise invisible fingerprints, sodium bisulphite helps
scientists visualize the spots in a cell>s genome that harbor methyl groups
and the spots that do not. The technique offers detailed views of DNA
methylation and can now be implemented on a large-scale due to advances in
high-throughput sequencing technologies.
With these advanced technologies, the scientists created DNA methylation
maps of embryonic stem cells, as well as cell types derived from them,
signifying the first such maps of mammalian cells. Several findings stood
out from careful analyses of the maps, the most notable of which was the
correlation between DNA methylation and histone methylation. Just as a
topographic map of steep terrain and a political map of countries and
borders may show similar patterns, chromatin and methylation maps can be
used individually, or, more effectively, together to see a clearer picture
of the molecular landscape. "In the past, these two types of epigenetic
marks were rarely studied together," said Tarjei Mikkelsen, a graduate
student at the Broad Institute and co-first author of the latest Nature
paper. "By examining them as a whole, we now have one of the first
integrated pictures of epigenetic changes during cellular development."
By perusing the maps, the researchers, led by Broad director Eric Lander,
were also able to pick out specific sites within the genome where
methylation fluctuates as cells develop, such as when embryonic stem cells
mature into neural cells. Peering more closely at these dynamic changes,
they identified certain sites associated with developmental genes that
become overly methylated.
"Hypermethylation can be a sign that nearby genes are inaccessible,
permanently shut off. And it is something that>s commonly observed in the
genomes of tumor cells," said Meissner. "These maps as well as the
approaches used to create them may help shed light on the role of DNA
methylation in human cancers."
Increasing the efficiency of reprogramming
DNA methylation was also at the core of the scientists' earlier paper,
published in July 3 print issue of Nature. That paper described several
molecular hurdles that impede a powerful technique in stem cell research - a
recently described laboratory procedure that can nudge adult cells into a
more primitive, stem-cell like state. This cellular "reprogramming" is now
the focus of intense interest as a potential way to artificially derive
embryonic stem cells from readily available adult tissues, such as skin. The
method, though, can be slow and inefficient, with most cells failing to be
reprogrammed.
Epigenetic marks such as DNA methylation are thought to act like a kind of
memory storage for cells, helping cells "remember" their identities by
keeping certain genes turned off and others on. If that>s true, then
reprogramming likely requires those memories to be reset or wiped clean,
allowing cells to assume new identities. During the course of their
research, the scientists discovered that some epigenetic information,
particularly DNA methylation, is especially difficult to expunge, hindering
the reprogramming process. They then showed that treating incompletely
reprogrammed cells with a drug that temporarily inhibits DNA methylation
could greatly increase the efficiency of the process.
"The same genes that are slow to respond to reprogramming are the genes we
see hypermethylated early on in development," Mikkelsen said "Improving the
low efficiency of the reprogramming process required circumventing this
mechanism without disabling it permanently."
Having a map of these mechanisms could help researchers orient themselves in
genomic space and develop additional methods to steer cells safely through
the entire reprogramming process. Perhaps, like explorers before them,
researchers today will also come across new discoveries along the way that
will fill in more of the epigenetic maps.
Other Broad researchers who contributed to these papers include Eric Lander,
Andreas Gnirke, Xiaolan Zhang, Bradley Bernstein, Andrey Sivachenko,
Hongcang Gu, Chad Nusbaum, and David Jaffe. Researchers from the Whitehead
Institute, Massachusetts General Hospital, and Harvard Medical School also
contributed to the research.
Links:
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature07107.html
Source: Harvard University
http://www.physorg.com/news134919094.html
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Robert Karl Stonjek |
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