Current Biology, Vol. 14, 911–916, May 25, 2004, 2004 Elsevier Ltd. All rights reserved.
DOI 10.1016/j .c ub . 20 04 . 04 .0 4 5
A Cluster of Arabidopsis Genes with a Coordinate
Response to an Environmental Stimulus
E. Jean Finnegan,1,* Candice C. Sheldon,1
Francois Jardinaud,1,2 W. James Peacock,1
and Elizabeth S. Dennis1
1
Commonwealth Scientific and Industrial Research
Organisation, Plant Industry
GPO Box 1600
Canberra ACT 2601
Australia
Summary
Vernalization, the promotion of flowering after pro-
longed exposure to low temperatures, is an adaptive
response of plants ensuring that flowering occurs at
a propitious time in the annual seasonal cycle. In Arabi-
dopsis, FLOWERING LOCUS C (FLC), which encodes
a repressor of flowering, is a key gene in the vernaliza-
tion response; plants with high-FLC expression re-
spond to vernalization by downregulating FLC and
thereby flowering at an earlier time [1–3]. Vernalization
has the hallmarks of an epigenetically regulated pro-
cess. The downregulation of FLC by low temperatures
is maintained throughout vegetative development but
is reset at each generation [4–6]. During our study of
vernalization, we have found that a small gene cluster,
including FLC and its two flanking genes, is coordi-
nately regulated in response to genetic modifiers, to
the environmental stimulus of vernalization, and in
plants with low levels of DNA methylation. Genes en-
coded on foreign DNA inserted into the cluster also
acquire the low-temperature response. At other chro-
mosomal locations, FLC maintains its response to ver-
nalization and imposes a parallel response on a flank-
ing gene. This suggests that FLC contains sequences
that confer changes in gene expression extending be-
yond FLC itself, perhaps through chromatin modifi-
cation.
Results and Discussion
The gene UPSTREAM OF FLC (UFC; At5g10150), which
has no known function, is located 4.7 Kb upstream of
FLOWERING LOCUS C (FLC; At5g10140) (Figure 1A).
Like FLC, UFC is downregulated in vernalized plants
(Figure 1B). The downregulation of UFC by vernalization
is less stably maintained than that of FLC. Although
FLC expression remains low for the vegetative life of
a vernalized plant, the expression of UFC returns to
approximately the same level as that in nonvernalized
plants by 28 days after the end of the vernalization treat-
ment (Figure 1C).
*Correspondence: jean.finnegan@csiro.au
2
Current address: Laboratoire Biotechnologie et Amélioration des
Plantes, Institut National Polytechnique de Toulouse, École Natio-
nale Supérieure Agronomique de Toulouse, Avenue de l’Agrobio-
pole, BP 107 Auzeville-Tolosane, F31326 Castanet-Tolosan Cedex,
France.
The observation that a cold treatment downregulates
these two genes raises the question of whether there
is a genome-wide downregulation of transcription in ver-
nalized plants. This is not the case. Two other genes
located on different chromosomes, CYCLOPHILIN (CYC;
At2g29960) and S-ADENOSYL METHIONINE SYN-
THASE (SAM; At4g01850), and a third gene, FORMAL-
DEHYDE DEHYDROGENASE (FDH; At5g43940), on the
same chromosome as FLC but at an unlinked location,
showed no change in transcript levels after vernalization
(Figure 1D; data not shown). This suggests that vernal-
ization affects particular regions of the genome, perhaps
only FLC and its neighboring genes.
FLC and UFC show parallel changes in expression in
nonvernalized plants of different Arabidopsis ecotypes,
which exhibit a wide range of flowering times and levels
of FLC transcript. Very late-flowering ecotypes, such as
San Fileu 2 (Sf2) and Pitztal, have higher levels of both
FLC and UFC transcripts than the early-flowering eco-
type, Landsberg erecta (L.er) (Figure 1E). The ecotype
C24, which has an intermediate-flowering time, has lev-
els of FLC and UFC transcripts between those of Sf2
and L.er. These genes show a similar developmentally-
regulated expression; they both have low-transcript lev-
els in germinated seeds, and their expression increases
markedly until the emergence of the first pair of leaves
(C.C.S., unpublished data).
Similarly, FLC and UFC are coordinately regulated
in response to different modifying genetic loci in late-
flowering mutants of Arabidopsis. Both genes are upreg-
ulated in the late-flowering mutant, flc-11, compared to
the parental line [2]. In this mutant, insertion of two
T-DNAs into the intergenic region between FLC and
UFC causes an approximately 2-fold increase in FLC
expression, and has an even greater effect on the ex-
pression of UFC (Figures 1A and 1E) [2]. In the late-
flowering L.er mutant, fca, the expression of both FLC
and UFC is elevated relative to the wild-type parent
(Figure 1E). Both genes show an even higher level of
transcription when VERNALIZATION2 (VRN2), which en-
codes a polycomb-group protein that is essential for
the repression of FLC by vernalization [4], is mutated in
the fca background (Figure 1E). In late-flowering eco-
types, the coordinate upregulation of these genes is
mediated through FRI activity. However, in the late-flow-
ering fca mutants, loss of the FCA protein, which has
previously been shown to repress FLC, is associated
with the upregulation of both FLC and UFC [2, 3, 7].
A possible explanation for the coordinate regulation
of FLC and UFC is that FLC acts as a transcriptional
activator of UFC or vice versa. However, this relationship
is unlikely, because in the early-flowering FLC null mu-
tant, flc-20, UFC transcript levels are comparable to
those in the later-flowering parental line (Figure 1F); fur-
thermore, overexpression of FLC does not lead to in-
creased transcription of UFC (data not shown). These
data indicate that UFC transcription is not dependent
on FLC protein levels. Similarly, in transgenic lines over-
expressing UFC, the level of FLC transcripts is un-
Current Biology
912

Figure 1. FLC and UFC Are Coordinately Regulated

(A) Map showing the FLC neighborhood, giving the relative location as indicated by the light lines and distance in kilobases (Kb) between
genes. The transcription direction of five genes is indicated by the arrows, which are located at the translation start. The position of the
Coordinate Gene Regulation in Arabidopsis
913

changed, indicating that UFC is not a transcriptional

regulator of FLC (Figure 1G).
There is evidence that proteins modulating FLC ex-
pression are chromatin associated, suggesting another
explanation for the coordinate regulation of these genes.
Transcription of FLC is dependent on PIE1, an Imitation
Switch (ISWI)-like protein from the SWI2/SNF2 family of
chromatin-remodeling ATPases [8]. FLC transcription
is repressed by VRN2, a polycomb protein that forms
repressive chromatin [4, 9, 10, 11], and by FCA, an RNA
binding protein [12]. The coordinate upregulation of this
cluster of genes in the fea mutant suggests that either
FCA, which has been shown to interact with AtSWI3B,
a component of a putative Arabidopsis chromatin-
remodeling complex [13], targets this complex to the
FLC domain by binding a guide RNA, or FCA regulates
processing of the mRNA encoding a chromatin-modifying
protein. It seems possible that chromatin structural
changes across a domain spanning FLC and UFC confer
the coordinate responses by changing the accessibility
of these genes for transcription.
The coordinate regulation of FLC and UFC might oc-
cur because these genes have related functions, as has
been reported for clustered genes showing tissue-spe-
cific expression [14–16]. However, there is no strong
evidence supporting this suggestion. Overexpression of
the UFC genomic clone does not alter flowering time
(Figure 1G; Table S1 in the Supplemental Data available
with this article online). Furthermore, constitutive ex-
pression of UFC does not alter the vernalization re-
sponse. After vernalization, the promotion of flowering
in plants expressing UFC under the control of a 35S
promoter, which does not respond to vernalization [5],
was equivalent to that seen in C24 plants, in which UFC
is downregulated by vernalization (Figure S1; Table S2).
Taken together, these data do not support a common
function for FLC and UFC in the regulation of flowering
time.
The coordinate regulation of FLC and UFC might result
solely from their proximity to one another in the genome.
To address this, we placed FLC and UFC in different
chromosomal locations in separate transgenic plants.
The FLC transgene showed a strong downregulation by
vernalization irrespective of its genomic location (Fig-
ures 1A and 2). When inserted at different chromosomal
locations, UFC also retained a vernalization response
(Figures 1A and 1G), but the vernalization-induced
downregulation of UFC was weaker than that seen for
the FLC construct. These data suggest that both FLC
and UFC contain DNA sequence elements that confer
Figure 2. An FLC Transgene Imposes a Vernalization Response on
the Adjacent Nos::NptII Gene
Northern blots showing that FLC responds to vernalization at heter-
ologous locations (upper) and that FLC imposes a vernalization
response on an adjacent Nos::NptII gene (lower). V ⫽ vernalized;
NV ⫽ nonvernalized.
a vernalization response. These sequences have been
mapped for FLC and lie within a 4.7 Kb region including
about 300 bp of promoter, the first two exons, and the
large first intron [5]. The sequences within UFC that
confer a vernalization response have not been defined,
but there are no extended regions of sequence similarity
between the regulatory regions of FLC and UFC.
The coordinate upregulation of these genes in differ-
ent genetic backgrounds defines a common expression
domain. The finding that both FLC and UFC respond to
vernalization when they are relocated suggests that the
coordinate downregulation of these genes could occur
through the binding of a transcriptional regulator com-
mon to each gene. A strong indication that vernalization
also affects an expression domain is the finding that
the Nos::NptII genes encoded by the T-DNAs inserted
between FLC and UFC in the flc-11 mutant take on a
vernalization response. In flc-11, both FLC and UFC are
downregulated by vernalization (Figure 3A), as are the
inserted Nos::NptII genes (Figures 1A and 3A). Repres-
sion of UFC and Nos::NptII does not persist through the
life of the plant (Figure 3A); the expression of both genes
is restored to that of the nonvernalized control by fifteen
days after the cold treatment (Figure S2). Twenty-five
days after the cold treatment, the level of FLC expres-
sion is 40% of the nonvernalized control, whereas the
expression of both UFC and NPTII is somewhat higher
than that in nonvernalized plants (Figure 3A). When in-
serted at other chromosomal locations that are unlinked
to a vernalization responsive locus, the Nos::NptII gene

T-DNA insertion in flc-11 is given. The heavy lines beneath the map indicate the extent of the FLC and UFC transgenes used in transformation
experiments, and the dashed line joining the arrowheads indicates the extent of the FLC domain.
(B) Northern blots showing FLC (right) and UFC (left) transcripts in nonvernalized and vernalized C24 plants and in plants with reduced levels
of DNA methylation (AMT) [31].
(C) Northern blots showing the recovery of UFC transcript levels after vernalization (left); FLC expression in the same plants is stably repressed
(right). V ⫹ n ⫽ vernalized ⫹ n days after vernalization.
(D) Northern blots showing CYC and SAM transcript levels in nonvernalized and vernalized plants.
(E) FLC (upper) and UFC (lower) are coordinately upregulated in late-flowering ecotypes (Sf2 and Pitztal) and late flowering mutants (fca, fca
vrn2 and flc-11). C24 is included on both blots for UFC expression, to provide a common reference.
(F) Northern blots showing UFC (left) and FLC (right) transcript levels in the flc null mutant, flc-20.
(G) Northern blots showing UFC (top), FLC (middle), and NptII (lower) transcript levels in plants transformed with a UFC genomic clone. V ⫽
vernalized; NV ⫽ nonvernalized. In each case, loading is indicated by the ethidium stained gel showing ribosomal RNA.
Current Biology
914

Figure 3. FLC Lies within a Chromosomal Domain that Is Downregulated by Vernalization

(A) Northern blots showing that the Nos::NptII genes (middle) inserted between FLC (right) and UFC (left) are downregulated in vernalized flc-
11 plants. V ⫹ n ⫽ vernalized ⫹ n days after vernalization.
(B) A Nos::NptII gene adjacent to a 35S::FLC::GUS transgene that does not respond to vernalization (upper) [5] is not downregulated by
vernalization (lower).V ⫽ vernalized; NV ⫽ nonvernalized.
(C) Semi-quantitative RT-PCR analysis of expression of FDH (left), At5g10130 (center), and At5g10160 (right) in nonvernalized and vernalized
fca plants. V ⫽ vernalized; NV ⫽ nonvernalized; ⫺ve is the no-template control; gDNA ⫽ genomic DNA.
(D) Semi-quantitative RT-PCR analysis of the expression of FDH (left), At5g10130 (center), and At5g10160 (right) in nonvernalized L.er and
fca plants. Controls are as for (C).

does not respond to vernalization (Figures 1G and 3B).
This suggests that the downregulation of NptII expres-
sion seen in vernalized flc-11 was a consequence of its
insertion in the FLC neighborhood, and this also sup-
ports the notion that FLC and UFC are located in a
common expression domain.
The coordinate expression of clustered genes has not
been reported in plants except in situations in which the
adjacent genes have been generated by localized-gene-
duplication events giving rise to a group of genes with
related function, such as the leghaemoglobin genes [17–
19]. Our data on the FLC region indicate that coordinate
regulation of adjacent genes does occur in plants. At
present, we have no data on the frequency of gene
clusters in plant genomes, but there are many examples
in mammals, nematodes, and Drosophila [14–16, 20–22].
However, the coordinate response of gene expression
in the FLC region has a special property, which is not
found with animal gene clusters, namely that the coordi-
nate expression is controlled not only by endogenous
signals provided by a number of other genes but also
by the environmental stimulus. The other special feature
that we have identified is that insertion of foreign DNA
carrying Nos::NptII into the FLC region caused this trans-
gene to acquire the low-temperature response of the
region.
To determine whether sequences in FLC and/or UFC
confer a vernalization response on flanking genes, we
monitored the expression of the Nos::NptII gene located
adjacent to either FLC or UFC transgenes in different
genomic locations (Figure S3). We found that the FLC
transgene imposed a vernalization-induced downregu-
lation on Nos::NptII (Figure 2) in the majority of genomic
locations (9/10) lines. In one single copy-insertion line,
Nos::NptII expression was unchanged after vernaliza-
tion, even though the FLC transgene was repressed
(data not shown), suggesting that flanking sequences
may modify the spreading effect of vernalization. When
the Nos::NptII marker was linked to the UFC gene at
different chromosomal locations, it was not downregu-
lated by vernalization, even though UFC itself was par-
tially downregulated (Figure 1G). The failure of UFC to
impose a vernalization-induced repression on the adja-
cent Nos::NptII gene may be because UFC showed
weaker autonomous repression than FLC, or it may be
because it lacks the sequences required for spreading
the vernalization response to adjacent genes.
We found that the vernalization responsive domain
around FLC at its normal location also extends down-
stream. Expression of the gene At5g10130, which en-
codes a protein with similarity to a pollen allergen and
is located 6.9 Kb downstream of FLC, is repressed in
vernalized plants (Figures 1A and 3C). In contrast, the
gene upstream of UFC did not respond to vernalization
Coordinate Gene Regulation in Arabidopsis
915
Figure 4. Decreased DNA Methylation Downregulates the Vernal-
ization-Responsive Gene Cluster that Includes FLC
Northern blots of RNA isolated from flc-11 plants showing that low
levels of DNA methylation downregulate genes in the FLC neighbor-
hood, UFC (left), Nos::NptII (center), and FLC (right).
(Figure 3C). These data map the vernalization responsive
domain to at least 3 genes spanning about 12 Kb in
wild-type plants. This domain can be extended by the
insertion of two Nos::NptII genes on a 20 Kb segment
between FLC and UFC (Figure 1A).
Decreased DNA methylation levels also cause the
downregulation of FLC (Figure 1B) [2]. UFC expression
is similarly decreased in plants with low levels of CpG
methylation compared to plants with normal methylation
levels (Figure 1B). In the flc-11 mutant, where the expres-
sion domain was extended by the 20 Kb insertion includ-
ing Nos::NptII, conditions of low methylation resulted
in the downregulation of FLC, UFC, and the inserted
Nos::NptII genes (Figure 4). DNA methylation can influ-
ence histone modification and vice versa, so the repres-
sion of gene activity could again be due to changes in
chromatin structure [23–28]. Because there is a common
chromosomal domain that responds to vernalization and
to conditions of low-DNA methylation, it is tempting to
speculate that this response involves demethylation of
DNA either within the domain itself or in the regulatory
sequences of transcription factor(s) regulating FLC ex-
pression. However, we could not detect changes in DNA
methylation of FLC regulatory sequences resulting from
either vernalization or in plants with low methylation
(E.J.F., unpublished data).
It is known that FLC transcription depends on an ISWI
chromatin-remodeling complex [8], and this may also
facilitate transcription of UFC and the downstream gene,
At5g10130 (Figure 3D), by opening the chromatin to tran-
scription machinery. The PHD domain protein, VIN3, has
recently been implicated in the establishment of the
vernalization-induced repression of FLC, and repression
is associated with loss of histone acetylation [10]. VIN3
binds sequences in both the FLC promoter and first
intron [10], but binding of VIN3 to UFC has not been
tested.
A second aspect of repression probably involves the
interaction of the polycomb-group protein, VRN2, and
sequences within the first intron of FLC [4, 5]. By analogy
with Drosophila, VRN2 is likely to be part of a complex
that modifies histone H3 by methylation of lysine 27 [29].
Consistent with this, methylation of histone H3 lysine
27 occurs within the promoter and first intron of FLC in
vernalized plants [9, 10]. Because UFC is not stably
repressed by vernalization, it may not have sequences
that interact with VRN2 or that are associated with
changes in histone modification.
The mechanism for transmission of the vernalization
response to adjacent genes remains unknown but most
likely involves some domain-wide change in chromatin
structure. In an animal system (rat), the spreading of
chromatin changes across an expression domain has
been observed in a cluster of neuronal specific genes
[15]. A corepressor complex associated with the REST/
NRSF-silencing factor (CoREST) recruits the molecular
machinery that imposes silencing across this chromo-
somal region, including genes that lack REST/NSRK
binding sites [15]. Similarly, the X chromosome of
C. elegans contains recruitment sites for the dosage-
compensation complex (DCC), which then spreads to
adjacent regions lacking DCC binding sites [30]. Our
data suggest that FLC contains sequences that bind
a vernalization responsive factor, similar in action to
CoREST or DCC, that facilitates the spread of repressive
chromatin from FLC to genes on either side, including
introduced genes. Further dissection of the FLC locus
may identify the sequences required for the transmis-
sion of the vernalization-induced repression to adjacent
genes.
Supplemental Data
Supplemental Data including Experimental Procedures, three fig-
ures, and two tables are available at http://www.current-biology.
com/cgi/content/full/14/10/911/DC1/.
Acknowledgments
The authors thank Xiaomei Zhu and Anna Conn for their excellent
technical assistance.
Received: March 11, 2004
Revised: March 20, 2004
Accepted: March 29, 2004
Published: May 25, 2004
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