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Science Forum Index » Bio Evolution Forum » News: Charting the epigenome
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| Robert Karl Stonjek |
 Posted: Fri Apr 18, 2008 7:34 am |
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Charting the epigenome
Until recently, the chemical marks littering the DNA inside our cells like
trees dotting a landscape could only be studied one gene at a time. But new
high-throughput DNA sequencing technology has enabled researchers at the
Salk Institute for Biological Studies to map the precise position of these
individual DNA modifications throughout the genome of the plant Arabidopsis
thaliana, and chart its effect on the activity of any of Arabidopsis'
roughly 26,000 genes.
"For a long time the prevailing view held that individual modifications are
not critical," says Joseph Ecker, Ph.D., a professor in the Plant Biology
laboratory and director of the Salk Institute Genomic Analysis Laboratory.
"The genomes of higher eukaryotes are peppered with modifications but unless
you can take a detailed look at a large scale there is no way of knowing
whether a particular mark is critical or not."
The Salk study, which appears today in the online issue of Cell, paints a
detailed picture of a dynamic and ever-changing, yet highly controlled,
epigenome, the layer of genetic control beyond the regulation inherent in
the sequence of the genes themselves.
Being able to study the epigenome in great detail and in its entirety will
provide researchers with a better understanding of plant productivity and
stress resistance, the dynamics of the human genome, stem cells' capacity to
self-renew and how epigenetic factors contribute to the development of
tumors and disease.
Discoveries in recent years made it increasingly clear that there is far
more to genetics than the sequence of building blocks that make up our
genes. Adding molecules such as methyl groups to the backbone of DNA without
altering the letters of the DNA alphabet can change how genes interact with
the cell's transcribing machinery and hand cells an additional tool to
fine-tune gene expression.
"The goal of our study was to integrate multiple levels of epigenetic
information since we still have a very poor understanding of the genome-wide
regulation of methylation and its effect on the transcriptome," explains
postdoctoral researcher and co-first author Ryan Lister, Ph.D.
The transcriptome encompasses all RNA copies or transcripts made from DNA.
The bulk of transcripts consists of messenger RNAs, or mRNAs, that serve as
templates for the manufacture of proteins but also includes regulatory small
RNAs, or smRNAs. The latter wield their power over gene expression by
literally cutting short the lives of mRNAs or tagging specific sequences in
the genome for methylation.
But before Lister could start to unravel the multiple layers of epigenetic
regulation that control gene expression, he had to pioneer new technologies
that allowed him to look at genome-wide methylation at single-base
resolution and to sequence the complete transcriptome within a reasonable
timeframe.
Collaborating scientists at the ARC Centre of Excellence in Plant Energy
Biology at the University of Western Australia in Perth developed a
powerful, web-based genome browser, which played a crucial role in unlocking
the information hidden in the massive datasets.
Cells employ a whole army of enzymes that add methyl groups at specific
sites, maintain established patterns or remove undesirable methyl groups.
When Lister and his colleagues compared normal cells with cells lacking
different combination of enzymes they discovered that cells put a lot of
effort in keeping certain areas of the genome methylation-free.
On the flipside, the Salk researchers found that when they knocked out a
whole class of methylases, a different type of methylase would step into the
breach for the missing ones. This finding is relevant for a new class of
cancer drugs that work by changing the methylation pattern in tumor cells.
"You might succeed in removing one type of methylation but end up with
increasing a different type," says Ecker. "But very soon we will be able to
look and see what kind of compensatory changes are happening and avoid
unintended consequences."
Previous studies had found that a subset of smRNAs could direct methylation
enzymes to the region of genomic DNA to which they aligned. Overlaying
genome-wide methylome and smRNA datasets confirmed increased methylation
precisely within the stretch of DNA that matched the sequence of the smRNA.
Conversely, heavily methylated smRNA loci tended to spawn more smRNAs.
"We looked at a plant genome but our method can be applied to any system,
including humans," says Lister. Although the human genome is about 20 times
bigger than the genome of Arabidopsis - plant biologists' favorite model
system not least because of its compact genome - Ecker predicts that within
a year or so, sequencing technology will have advanced far enough to put the
3 billion base pairs of the human genome and their methyl buddies within
reach.
"This really is just the beginning of unmasking the role of these powerful
epigenetic regulatory mechanisms in eukaryotes," says Ecker.
Source: Salk Institute
http://www.physorg.com/news127653977.html
Comment:
It is interesting to note that crest has 26,000 genes, humans have around
35,000.
Posted by
Robert Karl Stonjek |
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