Although most eukaryotic genomes lack operons, occasionally clusters of genes are discovered that are related in function. Now, a metabolic operon-like gene cluster has been described in Arabidopsis thaliana that is needed for triterpene synthesis

Amoutzias, Grigoris

Van de Peer, Yves

Although most eukaryotic genomes lack operons, occasionally clusters of genes are discovered that are related in function. Now, a metabolic operon-like gene cluster has been described in Arabidopsis thaliana, that is needed for triterpene synthesis

Elsevier - Publisher Connector 

Registering the reference gene expres-
sion from hundreds of embryos permitted
the registration of the second gene’s ex-
pression, producing an average 3D ex-
pression map for gene X or Y. Although
the in situ hybridizations of gene X and
Y were conducted independently, their
expression patterns can be overlaid and
comparedas their average expressionpat-
terns are mapped to a commonmodel (the
virtual embryo). This allows spatial multi-
plexing in silico at an almost infinite scale.
The authors performed this expression
mapping for 95 genes during a 50 min in-
terval prior to gastrulation—an impressive
body of work. The results are very excit-
ing: 3D virtual images that look almost
identical to simultaneous in situs per-
formed in the same embryo. It is very dif-
ficult to quantitate how similar ‘‘almost
identical’’ is. The authors assessed this
by comparing the variability in expression
of two genes (giant and eve) measured in
the same embryo (a standard double
in situ hybridization) to that inferred by
their registration method for the two
genes imaged in different embryos. The
variability in expression was measured
by grouping nuclei that have similar ex-
pression levels of giant into bins and
then looking at the average expression
levels of eve. The maximum standard de-
viation of eve expression in all bins was
0.21 for the ‘‘real’’ double in situs and
0.3 in the virtual embryo, while the maxi-
mum expression levels of eve and giant
deviate by <7% between the two ap-
proaches. By these two criteria, the virtual
embryo provides an accurate average
quantitation of gene expression in 3D.
Many studies have tried to reconstruct
gene regulatory networks based on ex-
pression data under the assumption that
a transcription factor and a target gene
will be temporally coexpressed for some
period of time or have a small temporal
shift in their expression. These studies
are primarily based on microarray profil-
ing data, as this has been the only global
quantitative data available. The extraction
of relative gene expression data using vir-
tual embryos opens a new avenue for in-
ferring regulatory connections at a cell-
based level. Given themuch higher spatial
resolution, these data, in combination
with other data such as transcription fac-
tor binding site occupancy, should vastly
improve the predictive power of regula-
tory models. There is a clear need to
move toward a quantitative protein atlas
of transcription factor expression, inte-
grated with quantitative measures of their
target genes’ mRNA expression. The
computational methods developed by
Fowlkes et al. (2008) are an important first
step in this direction.
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Developmental Cell
PreviewsTogether We Stand: Genes Cluster to Coordinate
Regulation
Grigoris Amoutzias1 and Yves Van de Peer1,*
1Department of Plant Systems Biology, VIB and Department of Molecular Genetics, Ghent University, Technologiepark 927,
B-9052 Ghent, Belgium
*Correspondence: yves.vandepeer@psb.ugent.be
DOI 10.1016/j.devcel.2008.04.006
Although most eukaryotic genomes lack operons, occasionally clusters of genes are discovered that are
related in function. Now, a metabolic operon-like gene cluster has been described in Arabidopsis thaliana
that is needed for triterpene synthesis.Traditionally, genes were considered to
be randomly distributed in eukaryotic
genomes, in stark contrast with prokary-
otes, where unrelated genes with related
functions are clustered in so-called op-
erons. However, in the last few years,
genomic data reveal that also in eukary-
otic genomes, genes can be physically
clustered. The best known example is
probably Caenorhabditis elegans, where
almost 15% of the genes are organized
in polycistronic operons, but also in yeast,640 Developmental Cell 14, May 2008 ª2008 Elsevier Inc.
Developmental Cell
PreviewsFigure 1. Triterpene Gene Clusters in Arabidopsis thaliana and A. lyrata
While the structure of three out of four genes is the same in both species, the structure of theA. lyrata homolog of At5g47980 is different (indicated by a split gene).
Furthermore, these latter homologs in both species differ much more than the others (see dS and dN values), whichmight suggest paralogy rather than orthology
(see tree). Noteworthy is also a large insertion of >100 kb (mostly transposons) in the cluster inA. lyrata,which ismissing inA. thaliana. dS, number of synonymous
substitutions per synonymous site; dN, number of nonsynonymous substitutions per nonsynonymous site.metabolic clusters have been observed
(Hurst et al., 2004; Wong and Wolfe,
2005; Yi et al., 2007). The identification
of clusters of genes with similar functions
or involved in the same pathway or biolog-
ical process raises intriguing questions
about the molecular mechanisms and
evolutionary pressures responsible for
such self-organization. It is generally con-
sidered that this kind of spatial genomic
organization allows for tightly coordinated
gene expression and for genetic linkage
of functionally related genes. Therefore,
the organization of functionally related
genes in clusters is expected to have an
evolutionary advantage for the organism.
In monocot plants, some metabolic
clusters have been uncovered, such as
the one for benzoxazinoid biosynthesis
in maize, diterpene biosynthesis in rice,
and triterpene biosynthesis in oat (Gierl
and Frey, 2001; Qi et al., 2004; Shimura
et al., 2007). In a recent paper in Science,
Field and Osbourn (2008) showed the
formation of a metabolic gene cluster for
triterpene biosynthesis in the dicot
Arabidopsis. The authors describe the
identification and functional characteriza-
tion of a metabolic pathway that is re-
sponsible for the synthesis and further
modification of a triterpene saponin
named thalianol. Triterpenes are second-
ary metabolites, which usually protect
plants against pests and diseases. One-
quarter of all Arabidopsis genes is pre-
dicted to be involved in secondary metab-
olism, but generally these metabolic
genes are not clustered in plants, with
the previously mentioned exceptions of
diterpene, triterpene and benzoxazinoid
biosynthesis clusters in rice, oat andmaize, respectively. Field and Osbourn
(2008) identified a genomic region that
contains four contiguous genes encoding
a 2,3 oxidosqualene cyclase (OSC), two
CYP450s, and a BADH acyltransferase
(see Figure 1). Interestingly, the oat
‘‘avenacin’’ cluster is also composed of
a monocot-specific OSC gene, a mono-
cot-specific CYP450, and a monocot-
specific acyltransferase, among other
genes, such as glycosyltransferases.
Using null insertionmutants, RNA interfer-
ence (RNAi) knockdowns, and GC-MS
analysis, Field andOsbourn coulddemon-
strate that the Arabidopsis gene cluster
indeed encodes a pathway for the synthe-
sis and further modification of thalianol.
However, they could not detect the prod-
uct that is predicted to be modified by
the fourth gene of the cluster, the acyl-
transferase BADH.
It has been proposed that one of the
consequences of the clustering of genes
with the same function or involved in the
same pathway is that their expression is
tightly coordinated at the chromatin level
(Hurst et al., 2004), and, indeed, the
expression of all four Arabidopsis genes
in the thalianol cluster is highly corre-
lated (r = 0.86). Furthermore, all four
genes are predominantly expressed in
the root epidermis, as is the case with
the genes in the oat avenacin cluster. In
addition, the four genes of the thalianol
cluster have marked histone H3 lysine 27
trimethylation, while this is not the case
for their immediate neighboring genes.
Biochemical pathways usually do not
form isolated networks that run in parallel,
but on the contrary are highly intercon-
nected (Pichersky and Gang, 2000).DevelopmentaChanges in expression levels and tissue
distribution of someenzymesmay result in
ectopic expression and disruption of other
established tissue-specificpathways. This
interference may happen because a small
number of enzyme groups have consider-
ably expanded through gene duplication.
The duplicates are optimized for a certain
substrate, but they can still have an effect
on other similar, but noncognate, sub-
strates. Indeed, Field and Osbourn (2008)
demonstrate that the ectopic overaccu-
mulation of intermediate products of the
thalianol pathway in above-ground tissues
led to severe dwarfing, whereas elevated
levels of the same products resulted in
longer roots than the wild type. Also, in
the case of the oat triterpene avenacin,
mutants of sad3 or sad4 glycosylation
have aberrant root morphology. Evidently,
tight regulation of these two similar triter-
pene pathways is required in order to
ensure controlled development, and this is
achieved by the formation of tightly regu-
lated gene clusters.
The question remains whether the root-
specific epidermal triterpene gene clus-
ters in oat and Arabidopsis have arisen
by chance, horizontal gene transfer, or
convergent evolution, or do they, on the
contrary, share common ancestry? Sta-
tistical tests show that the probability of
finding five loci of saponin biosynthesis
within 3.6 cM in oat, assuming a random
distribution of genes, is extremely low
(Qi et al., 2004). Although no equivalent
analysis has been performed for the
thalianol gene cluster in Arabidopsis, it
seems that coincidental clustering also
here can be excluded. Triterpene sa-
ponins are widely found in eudicots,l Cell 14, May 2008 ª2008 Elsevier Inc. 641
Developmental Cell
Previewswhereas in cereals and grasses, they do
not seem to be present, with the excep-
tion of the Avena (oat) genus. A series of
DNA and RNA blot analyses in several
cereals did not identify any orthologs of
the avenacin Sad1 gene (Qi et al., 2004).
Of note, oat possibly diverged from the
eudicots about 150 million years ago. It
has been demonstrated that extensive
gene loss of secondary metabolite syn-
thases in microorganisms could mistake
a case of common ancestry for horizontal
gene transfer or convergent evolution
(Rantala et al., 2004). However, phyloge-
netic analyses of the avenacin and thalia-
nol pathways show that the genes of each
pathway are monocot and eudicot spe-
cific, respectively. Therefore, Field and
Osbourn (2008) exclude horizontal gene
transfer from bacteria or other organisms.
Unless we are dealing with a case of ram-
pant gene duplication, rapid neofunction-
alization, and gene losses of the ancestral
genes, which actually might not be so far-Glucose Restrictio
but without Buildin
Carles Canto´1,2 and Johan Auwerx1,2,3,*
1Institut de Ge´ne´tique et de Biologie Mole´cula
2Ecole Polytechnique Fe´de´rale de Lausanne;
3Institut Clinique de la Souris, F-67404 Illkirch
*Correspondence: auwerx@titus.u-strasbg.fr
DOI 10.1016/j.devcel.2008.04.012
The two metabolic sensors AMPK
Developmental Cell, the signaling m
the myogenic program. These obse
One of the most amazing features of skel-
etal muscle is its high plasticity, enabling it
to respond to changes in activity, injury, or
degeneration. This plasticity is largely due
tomuscle stem cells, better known as sat-
ellite cells, residing beneath the basal
lamina of adult skeletal muscle, closely
juxtaposed against the muscle fibers (Le
Grand and Rudnicki, 2007), which have
the ability to modulate muscle growth
and differentiation. Satellite cells in adult
skeletal muscle are normally quiescent,
642 Developmental Cell 14, May 2008 ª200fetched for secondary metabolism, the
most reasonable scenario is convergent
evolution and repeated de novo synthesis
of the avenacin and thalianol gene clus-
ters, as suggested by the authors. Cases
of convergent evolution have been re-
ported before for regulatory networks
involved in animal development (Amout-
zias et al., 2004) or for the formation
of pathways of secondary metabolism
(Pichersky and Gang, 2000). Never-
theless, the birth of clusters of functionally
related genes with tightly coordinated ex-
pression seems a rather rare event in eu-
karyotic genomes, but, undoubtedly, up-
coming plant genomes will shed more
light on fundamental questions regarding
the structure and evolution of such gene
clusters (see for example Figure 1).
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Together We Stand: Genes Cluster to Coordinate Regulation 

Ghent University Academic Bibliography

Together we stand: genes cluster to coordinate regulation

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