[extropy-chat] Epignomics/epigenetics- Nature Vs Nurture re-visited

Extropian Agroforestry Ventures Inc. megao at sasktel.net
Sun Dec 21 17:30:35 UTC 2003


>From Pagees 10 and 12 of Vol3#9 Nov/Dec 2003 PharmaGenomics
http://www.pharmagenomicsonline.com

Sorry article is not posted to the web but this item merits ongoing
discussion
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New Research Thrusts Epigenetics into the Drug and Diagnostic Spotlight
"Study results in this emerging field could pique the interest - and
open the pockets - of big pharma"

Recent research conducted at Duke University (Durham, NC, USA) into gene
methylation has revealed the correlation between a pregnant female's
diet and gene function in her offspring - findings that not only advance
our understanding of nutritional intake and susceptibility to disease
but also have implications for the application of epignetics to the
discovery of new drug therapeutics.

Epigenetics , as defined in the 10 august 2001 issue of SCIENCE, is the
study of inheritable changes in gene function that occur without a
change in DNA sequence.
The research team at Duke University, led by Randy Jirtle, professor of
the departments of radiation, oncology and pathology, focused its work
on Agouti mice, a strain of mouse with active genes that are linked to a
yellow-colored coat, as well as to obesisty, diabetes and cancer.  The
female mice were given extra vitamins and supplements - B12, folic acid,
choline and betaine - that affected methylation of these particular
genes.  Methyl groups are derived entirely from the foods people eat;
methylation allows environmental factors to tweak gene expression
without creating permanent mutations.  The supplements interacted with
the methyl group attached to a chromasome and altered the gene
expression by making the strands of DNA coil tight enough to cease
function.  The Agouti's offspring were born with a normal, brown-colored
coat and no inherited predispostion for obesity, diabetes or cancer.

"Our mouse study provided the first evidence that nutritional
supplementation during pregnancy can determine adult susceptibility to
diseases by altering the methylation of transposons adjacent to
housekeeping genes", says Jirtle.  "Thus, retroposons and also
imprinting regulatory elements of imprinted genes now can be considered
as genomic targets that link nutrition during early development with
adult disease susceptibility."

The next step in this project will be to define those epigenetically
liable targets in humans that result in diseases such as cancer, autism,
and bipolar disease.  The studies need to be done in humans because the
position of the retroposons and the imprinting regulatory elements are
different in each species.  Jirtle believes that identifying the targets
involved in epignetic deregulation will have a tremendous impact on the
drug discovery industry because it will delineate novel signaling
pathways mechanistically involved in these diseases and will result in a
completely different concept of drug design - altering epignetic
profiles rather than blocking enzymes or receptors.

"Our findings proved the important principle that environmental
exposures during early development can result in dramatic phenotype
changes in adulthood via altered DNA methylation," Jirtle says.  "This
will cause scientists to think differently about the etiology of chronic
diseases and the role of the environment in the disease process.  It
also will significantly enhance the visibility and credibility of
epignetic research".

Also advancing epignetic research is the the work being done by the
Human Epigenome Consortium, a collaboration between Epigenomics AG
(Berlin, Germany) and the Wellcome Trust Sanger Institute (Hinxton,
Cambridge, UK).
A pilot study, funded by the European Union, of methylation patterns in
the major histocompatibility complex (MHC) recently was completed.  The
sucess of this research led to the launch of the Human Epigenome Project
(HEP), the goal of which is to identify and describe sites in the human
genome at which cytosine bases are modified by DNA methylation.

The HEP pilot study began in 2000.  Researchers developed a pipeline for
large-scale methylation analysis using 150 expressed genes of MHC human
chromasome 6 as a model.  "The results now are being analysed and
prepared for publication," says Stephen Beck, head of human sequencing
at the Sanger Institute.  "[The results] confirmed our prediction that
methylation patterns are tissue specific.  The prescence of methylation
variable positions, we believe, will significantly increase our ability
to understand and diagnose disease".

According to the consortioum's web site, data analysis is broken down
into five steps.  First, genomic DNA goes through a bisulphite treatment
that converts non-methylated cytosines into a different base - uracil.
Next, the treated DNA is amplified in a polymerase chain reaction (PCR)
using bisulphite specific primers.  Third, the PCR products are
sequenced.  Then, the generated trace files go through data
normalization specific for bisulphite-converted sequences.  Lastly,trace
files are visualized or shown in data.

HEP researchers are working with Epigenomics' proprietary
high-throughput technology, which involves DNA methylation assays that
can run on microarrays, real-time PCR and primer-extension-based
products.  The consortium anticipates that the project will be completed
in five years.

The project is expected to yield commercial benefits in the diagnostic
sector.  "As far as we know, it has not yet been applied for extensive
drug or target discovery, but because this is a conceivable approach, we
might see it happen in the future". says Epignomics CSO Kurt Berlin.

Jirtle says he believes the effect of epignetics on the drug discovery
industry will be "massive; however, most of the pharmaceutical companies
just don't realize that yet".   The diseases that most likely result
from epignetic deregulation are cancer, autism and diabetes.  Therefore,
these diseases are likely to be the first targets of epignetic-derived
drugs.  Jirtle says, "It will probably be some time before we see
epigenetic-derived therapeutic or diagnostic pharmaceuticals because we
are just beginning to define disease-causing epigenetic mutations, and
the pharmaceutical industry is still not taking epignetics very
seriously".






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