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© 2001 Nature Publishing Group http://genetics.nature.com
© 2001 Nature Publishing Group http://genetics.nature.com
In embryos lacking Gcnf, Oct4 has an
expanded range of expression in the posterior end of the embryo and is also
expressed in the hindbrain region (see figure). Despite this expanded Oct4 expression pattern, some development proceeds
normally, suggesting that Oct4 may be
necessary, but not sufficient, for maintenance of the pluripotent state. Nevertheless, it will be interesting to see if expanded
Oct4 expression in Gcnf-deficient
embryos, particularly in the posterior
region, results in increased numbers of
germ cells being formed.
Gcnf may be involved in starting the
process of Oct4 repression, but it may not be
the only factor that can maintain repression. In fact, in Gcnf-deficient embryos,
Oct4 still remains repressed in much of the
embryo even though Gcnf is absent. That
repression could be maintained by other
orphan receptors such as Coup-TfI and
Coup-TfII, but could also be brought about
by epigenetic mechanisms such as promoter
methylation or histone deacetylation. In
fact, downregulation of Oct4 expression is
associated with promoter methylation11.
Recent studies suggest that DNA methylation can synergize with histone deacetylation in repressing gene expression12. It is
intriguing then that nuclear receptors such
as Gcnf, together with co-repressors, can
associate with histone deacetylases that play
a critical role in the chromatin remodeling
associated with gene silencing13–15. So perhaps Gcnf flicks the switch that triggers
Oct4 promoter methylation and histone
deacetylation. The resultant chromatin
remodeling would close and lock the Oct4
promoter and shut down Oct4 expression.
The identification of Gcnf as a repressor of
Oct4 undoubtedly raises more questions
than it answers, but the great thing is that
now there are hypotheses about Oct4 regulation that can be tested experimentally.
Watch this space
Over the last couple of years, two distinct
but related fields have figured greatly in
the scientific news headlines—stem cells
and cloning. In both fields, Oct4 looms
large. For stem-cell biologists, some of the
critical issues concern our ignorance of
the fundamental nature of stem cells.
What are the critical factors required for
self-renewal of stem cells or maintenance
of stem cells in an undifferentiated state?
What are the real differences between
pluripotent stem cells from embryos and
stem cells derived from adults? One of the
answers is clearly Oct4.
For the cloning field, a major issue is the
need to understand what is required to
transform a nucleus that is restricted in
potency into a nucleus that is totipotent
and can recapitulate development. Put
another way, what are the differences
between a somatic (restricted) nucleus
and a germline (totipotent) nucleus? One
of the answers, again, is Oct4. Understanding what this factor does to regulate
developmental potency is central to both
fields of study. The identification of a
nexus between Oct4 and Gcnf provides
some critical clues as to how the differences between pluripotent cells and differentiated cells are established and
maintained. Stay tuned!
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Pharmacogenetics: more than skin deep
Howard L. McLeod
Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
e-mail: [email protected]
It is well known that the efficacy of certain drugs varies from individual to individual, depending in part on variation in the genes
that encode drug metabolizing enzymes. Whereas ethnic and geographic differences are commonly used to classify drug
response, new results show that more accurate and robust genetic clusters—identified by genotyping a modest number of neutral markers—can be inferred with no prior knowledge of ethnicity. Such an approach may eventually become a part of drug evaluation and clinical practice.
The ongoing identification of singlenucleotide polymorphisms (SNPs) has produced a greater understanding of the sources
of genetic variability1. One area that will
probably benefit from this effort is pharmacogenetics—the inherited component of
variability in drug disposition, efficacy and
toxicity. Geographic, ethnic and racial differences in the frequency of variant alleles
provide a mechanistic basis for at least some
of the observed clinical differences in pharmacokinetics or drug effect between popunature genetics • volume 29 • november 2001
lations2–4. On page 265 of this issue, James
Wilson and colleagues5 compare the relative
effectiveness of two methods of identifying
clusters of people who have distinct patterns
of drug-metabolizing enzyme SNPs. They
show that clusters identified by genotyping
(using microsatellite DNA) are far more
robust than those identified using geographic and ethnic labels. These findings
suggest both the power, and possible limitations, of a population genetic approach to
drug response.
DNA-based protocols are already in
place for the prospective prevention of
severe toxicity from some medications.
For example, homozygous mutation in
the gene encoding thiopurine methyltransferase brings a high risk (near 100%)
of severe toxicity in patients receiving
standard doses of 6-mercaptopurine or
azathioprine6. Genetic screening of those
patients who might receive these drugs for
the treatment of leukemia or rheumatic
disease, or to avoid rejection of trans247
© 2001 Nature Publishing Group http://genetics.nature.com
news & views
planted organs, may prevent potentially
life-threatening toxicity6. Similar PCRbased assays can be carried out to determine the proper dose of the anticoagulant
warfarin, the odds of pain relief from
codeine and other clinical phenotypes that
are influenced by SNP status1,7.
Wilson and colleagues5 assess the representation of drug-metabolizing enzyme
variants through a population genetic
approach. Genotype analysis was carried
out using microsatellite repeats from chromosome 1 (16 markers) and the X chromosome (23 markers) in 354 individuals
from eight populations. These included
Caucasian (Norwegian, Ashkenazi Jew,
Armenian), Black (Bantu, Ethiopian,
Afro-Caribbean) and Asian (Chinese, New
Guinean) groups. The genetic data were
then subjected to hierarchical clustering
analysis (using the program STRUCTURE) to objectively determine distinct
groups of individuals. Chromosome 1
markers gave clearer resolution than did
the X chromosome, although no population was found to segregate completely
with one of the four derived clusters.
In addition, they show that inferred
groupings based on the panel of chromosome 1 markers are much more successful
at identifying people with distinct drugmetabolizing enzyme SNP patterns than
an approach based solely on an ethnic or
geographic label. This stands in contrast
both to the common use of ethnicity as a
variable in the evaluation of clinical studies and the literature that segregates populations into distinct ethnic or racial
248
© 2001 Nature Publishing Group http://genetics.nature.com
BOB CRIMI
groupings. The results highlight the
genetic diversity of individuals, which is
far beyond that which can be attributed to
skin color or geography.
This work also provides impetus for
defining the underlying molecular basis of
apparent racial or ethnic influences on
clinical phenotypes. For example, a recent
study of an angiotensin-converting
enzyme inhibitor for heart failure
described a lack of benefit for black
patients, but a significant benefit for white
patients8. This was not an ‘all-or-none’
phenomenon; 14% of black patients benefited compared with 49% of white
patients. The genetic basis of the racial differential in drug efficacy may also explain
why 51% of white patients were not helped
by this therapy. It is no surprise that skin
pigment is a lousy surrogate for drugmetabolism status or most any aspect of
human physiology9. There is a reason for
this clinical observation, but it is not as
simple as geography, ethnicity or such.
Wilson et al.5 show that genetic clustering is preferable to less objective measures,
but there is no clustering algorithm that
can provide a predictive surrogate for all of
the drug-metabolizing enzyme SNPs.
With the growing importance of SNPs and
other genomic variants for guiding the
selection of therapy, identification of disease risk, prevention of drug toxicity and
other aspects of medical decision-making,
there is no escaping the need to carry out
individual genotype analysis for each SNP
in individual patients. There will be no
shortcuts or derived genomic map in the
context of pharmacogenetics. As such, we
must await improvements in the throughput, speed and cost of genotyping in order
to bring this exciting academic exercise
into medical application.
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nature genetics • volume 29 • november 2001