Download Letter Neighboring Genes Show

Neighboring Genes Show Interchromosomal Colocalization
after Their Separation
Zhiming Dai,1 Yuanyan Xiong,*,2 and Xianhua Dai1
1
Department of Electronics and Communication Engineering, School of Information Science and Technology, Sun Yat-Sen
University, Guangzhou, China
2
State Key laboratory for Biocontrol, Sun Yat-Sen University, Guangzhou, China
*Corresponding author: E-mail: [email protected].
Associate editor: John Parsch
Abstract
The order of genes on eukaryotic chromosomes is nonrandom. Some neighboring genes show order conservation among
species, while some neighboring genes separate during evolution. Here, we investigated whether neighboring genes show
interactions after their separation. We found that neighboring gene pairs tend to show interchromosomal colocalization
(i.e., nuclear colocalization) in the species in which they separate. These nuclear colocalized separated neighboring gene
pairs 1) show neighborhood conservation in more species, 2) tend to be regulated by the same transcription factor, and 3)
tend to be regulated by the same histone modification. These results suggest a mechanism by which neighboring genes
could retain nuclear proximity after their separation.
Key words: gene order, neighboring genes, nuclear colocalization.
Letter
Gene order is nonrandom in eukaryotic genomes (Hurst et al.
2004). Closely located genes show more similar gene expression patterns than randomly chosen gene pairs. The general
phenomenon of coexpression of neighboring genes has been
reported in several model eukaryotes such as Saccharomyces
cerevisiae (Kruglyak and Tang 2000; Fukuoka et al. 2004;
Lercher and Hurst 2006), Caenorhabditis elegans (Lercher
et al. 2003), Drosophila melanogaster (Boutanaev et al. 2002;
Spellman and Rubin 2002; Bailey et al. 2004; Kalmykova et al.
2005), and human (Singer et al. 2005; Li et al. 2006; Semon and
Duret 2006). In the mouse genome, tissue-specific expressed
genes aggregate in clusters on chromosomes (Williams and
Hurst 2002). Genes essential for viability also show strong
clustering in C. elegans, S. cerevisiae, and mouse (Kamath
et al. 2003; Pal and Hurst 2003; Hentges et al. 2007). Genes
related to similar functions tend to cluster: genes from the
same metabolic pathway also tend to cluster in eukaryotes
(Lee and Sonnhammer 2003). However, recent evidence has
indicated that genes with similar expression profiles show no
conservation in gene order (Weber and Hurst 2011) and
adjacent coexpressed genes are more likely to become rearranged (Liao and Zhang 2008).
There are several factors proposed to be responsible for the
nonrandom gene order. Coexpression of neighboring genes
constrains gene order. Many divergently transcribed oriented
neighboring genes show coexpression in S. cerevisiae and
human, suggesting that bidirectional promoters play a role
in regulating coexpression (Trinklein et al. 2004; Yang et al.
2007; Kensche et al. 2008). Intergenic distance is a strong
determinant of nonrandom gene order in yeast (Poyatos
and Hurst 2007). Chromatin structure, including nucleosome
positioning, chromatin remodeling, and histone modifications, could explain the coexpression of closely located
genes in Arabidopsis thaliana and S. cerevisiae (Batada et al.
2007; Chen et al. 2010). The coexpression is also attributable
to the shared regulation by the same transcription factor (TF)
in eukaryotic genomes (Michalak 2008). TF regulation constrains gene order on yeast chromosomes (Janga et al. 2008).
The three-dimensional (3D) organization of chromosomes
is nonrandom within the eukaryotic nucleus, and individual
chromosomes occupy distinct territories (Lanctot et al. 2007).
Genes on different chromosomes could be brought into close
proximity by interchromosomal interactions (Lomvardas
et al. 2006). Recent advances in experimental methods have
made it possible to study the 3D architecture of the whole
genome in the nuclear space with a high resolution (Duan
et al. 2010; Dixon et al. 2012; de Wit et al. 2013; Nagano et al.
2013). Genes showing nuclear colocalization tend to be regulated by similar transcriptional programs. Target genes of
one TF tend to show nuclear proximity, and TFs with
highly colocalized targets are expressed higher than those
whose targets are not spatially clustered in yeast (Ben-Elazar
et al. 2013). The colocalization of TF target genes could
strengthen TF regulation (Dai and Dai 2012) and is required
for transcription of some genes (Fanucchi et al. 2013). As a
consequence, genes spatially clustered tend to show gene
coexpression in human (Szczepińska and Pawlowski 2013).
Functionally related genes show an enrichment of interchromosomal colocalization in yeast (Homouz and Kudlicki 2013).
Coexpression of neighboring genes is maintained after the
neighborhood is broken up (Wang et al. 2011). This suggests
that gene pairs that were genomic neighbors in the evolutionary past, but are separated now, might be still regulated
by similar transcriptional programs. It is interesting to ask
whether neighboring genes show other links after their separation. In this study, we examined whether neighboring
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e-mail: [email protected]
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Mol. Biol. Evol. 31(5):1166–1172 doi:10.1093/molbev/msu065 Advance Access publication February 6, 2014
Interchromosomal Colocalization of Separated Neighboring Genes . doi:10.1093/molbev/msu065
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FIG. 1. Neighboring genes show interchromosomal colocalization after their separation. (A) Phylogeny of species included in this study (adapted from
Byrne and Wolfe [2005]). (B) A brief illustration of this study. (C) Distributions of the frequency of neighboring gene pairs showing interchromosomal
colocalization after their separation. The dot is for the realistic data, while the line depicts the distributions for 100,000 randomized experiments. The
statistical significance is indicated.
genes show interchromosomal colocalization after their separation. To address this, we focused on yeasts including the
baker’s yeast S. cerevisiae. So far, S. cerevisiae has been the
main model species in the studies of gene order as tremendous amounts of molecular knowledge and data are available.
Results
Neighboring Genes Show Interchromosomal
Colocalization after Their Separation
We identified separated neighboring gene pairs (11,693 pairs)
from gene order data in 17 yeast species (fig. 1A) (see details
in Materials and Methods section). We examined whether
neighboring genes show interchromosomal colocalization
(Duan et al. 2010) after their separation (fig. 1B). We found
that 658 of 11,693 (~5.6%) separated neighboring gene pairs
show interchromosomal colocalization in S. cerevisiae (supplementary table S1, Supplementary Material online). We
next generated random gene pairs to test the statistical significance of this observation (see details in supplementary
materials, Supplementary Material online). If the interchromosomal colocalization is not the feature of separated neighboring gene pairs, the random gene pairs should show
a similar degree of interchromosomal colocalization. We repeated the randomized experiment 100,000 times. We found
that the frequencies of interchromosomal colocalization for
all these randomized experiments are smaller than that
of separated neighboring gene pairs (P < 105 , fig. 1C).
We identified separated neighboring gene pairs on the
same chromosome and found that they show more intrachromosomal colocalization than expected by chance
(P ¼ 105 , supplementary fig. S1, Supplementary Material
online). Similar results could be reproduced when using another version of interchromosomal and intrachromosomal
interaction data (supplementary fig. S2, Supplementary
Material online).
Separated Neighboring Gene Pairs Showing
Interchromosomal Colocalization Show Neighborhood
Conservation in More Species
We examined the neighborhood conservation of separated
neighboring gene pairs showing interchromosomal colocalization. We found that separated neighboring gene pairs having
interchromosomal colocalization show neighborhood conservation in more species than separated neighboring gene pairs
not having interchromosomal colocalization (P ¼ 0:002,
Mann–Whitney U test, fig. 2A). We next examined the relationship between separated neighboring gene pairs and their
neighboring genes in S. cerevisiae. Genes in separated neighboring gene pairs and neighboring genes in S. cerevisiae of their
paired genes tend to show neighborhood in other yeast
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FIG. 2. Separated neighboring gene pairs showing interchromosomal colocalization tend to show neighborhood conservation in more species.
(A) Average values that correspond to the number of species in which gene neighborhood occurs are shown for separated neighboring gene pairs
showing interchromosomal colocalization and separated neighboring gene pairs not showing interchromosomal colocalization. (B) Average values that
correspond to the number of species in which gene neighborhood occurs are shown for interchromosomal colocalized separated neighboring genes and
the neighboring genes of their paired genes in Saccharomyces cerevisiae, and non-interchromosomal colocalized separated neighboring genes and the
neighboring genes of their paired genes in S. cerevisiae. (C) Average values that correspond to the number of species in which gene neighborhood occurs
are shown for separated neighboring gene pairs showing interchromosomal colocalization, and interchromosomal colocalized separated neighboring
genes and their neighboring genes in S. cerevisiae. Error bars were calculated by bootstrapping. The statistical significant values calculated from Mann–
Whitney U test are indicated.
species. The numbers of species in which these neighborhoods
occur are bigger for separated neighboring gene pairs showing
interchromosomal colocalization, compared with separated
neighboring gene pairs not showing interchromosomal colocalization (P < 108 , Mann–Whitney U test, fig. 2B). These
results demonstrate that if separated neighboring gene pairs
show interchromosomal colocalization in S. cerevisiae, they
show neighborhood conservation in more species and show
neighborhood conservation with each other’s S. cerevisiae
neighboring gene in more species. This high neighborhood
conservation might constrain neighboring gene pairs to
show interchromosomal interactions after their separation.
However, this conservation is weaker than the neighborhood
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conservation of S. cerevisiae linear neighboring genes
(P < 10113 , Mann–Whitney U test, fig. 2C). These results
suggest that interchromosomal interaction of separated
neighboring gene pairs is a modest link, weaker than linear
neighboring genes but stronger than separated neighboring
gene pairs not showing interchromosomal interaction.
Separated Neighboring Gene Pairs Showing
Interchromosomal Colocalization Tend to be Bound
by the Same Transcription Factor
We asked what cause separated neighboring gene pairs to
show interchromosomal colocalization. TFs have been shown
Interchromosomal Colocalization of Separated Neighboring Genes . doi:10.1093/molbev/msu065
to bind gene clusters on eukaryotic chromosomes (Janga et al.
2008). We asked whether interchromosomal colocalization of
separated neighboring gene pairs is associated with TF coregulation. Using genome-wide TF binding data in S. cerevisiae
(Harbison et al. 2004), we found that separated neighboring
gene pairs showing interchromosomal colocalization tend to
be regulated by the same TF relative to separated neighboring
gene pairs not showing interchromosomal colocalization (hypergeometric P ¼ 0:02, fig. 3A). The resulting TFs include 28
TFs and do not show a significant preference for one specific
TF (supplementary table S2, Supplementary Material online).
However, the observation above might be just a general feature of interchromosomal colocalized gene pairs regardless of
whether separated neighboring gene pairs or not. To test this
possibility, we identified all interchromosomal colocalized
gene pairs in S. cerevisiae. We found that separated neighboring gene pairs showing interchromosomal colocalization still
show tendency to be regulated by the same TF relative to all
interchromosomal colocalized gene pairs (hypergeometric
P < 105 ). These results indicate that coregulation by the
same TF is a feature of separated neighboring gene pairs
showing interchromosomal colocalization.
Separated Neighboring Gene Pairs Showing
Interchromosomal Colocalization Tend to Have
Similar Histone Modifications
We examined whether separated neighboring gene pairs
showing interchromosomal colocalization have similar histone modification levels. Using genome-wide histone modification data in S. cerevisiae (Pokholok et al. 2005; O’Connor
and Wyrick 2007), we found that separated neighboring gene
pairs showing interchromosomal colocalization show higher
similarity in histone modification levels than separated neighboring gene pairs not showing interchromosomal colocalization (P < 0:05, Mann–Whitney U test, fig. 3B). Moreover,
separated neighboring gene pairs showing interchromosomal
colocalization show higher similarity in histone modification
levels than all interchromosomal colocalized gene pairs
(P < 103 , Mann–Whitney U test, supplementary fig. S3,
Supplementary Material online). These results indicate that
coregulation by the same histone modification is a feature of
separated neighboring gene pairs showing interchromosomal
colocalization. Interestingly, separated neighboring gene pairs
showing interchromosomal colocalization have higher levels
of H3K56 acetylation levels on ORF while have lower levels of
H3K79 trimethylation levels on promoter (P < 104 , Mann–
Whitney U test, fig. 3C). They should be regulated by similar
acetyltransferase and demethyltransferases. In addition, they
show comparable transcriptional activity (Holstege et al.
1998) with the other genes (P ¼ 0:2, Mann–Whitney U test).
Separated Neighboring Gene Pairs Showing
Interchromosomal Colocalization Show Gene
Coexpression
Using a combined gene expression data set on 112 time
points during the condition (Cho et al. 1998; Spellman
et al. 1998; Gasch et al. 2000) similar to that where
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interchromosomal interactions data were measured in
S. cerevisiae, we found that separated neighboring gene
pairs showing interchromosomal colocalization show higher
coexpression (P ¼ 0:05, Mann–Whitney U test, fig. 3D).
Separated neighboring gene pairs showing interchromosomal
colocalization show weaker coexpression with their neighboring genes in S. cerevisiae than those between separated neighboring gene pairs not showing interchromosomal
colocalization and their neighboring genes in S. cerevisiae
(P ¼ 0:02, Mann–Whitney U test, fig. 3E). Gene nuclear location might be associated with gene expression noise (Singh
et al. 2011). However, separated neighboring gene pairs showing interchromosomal colocalization have comparable similarity in gene expression noise (Newman et al. 2006) with
separated neighboring gene pairs not showing interchromosomal colocalization (P ¼ 0:9, Mann–Whitney U test).
Discussion
In this study, we investigated whether neighboring genes still
show interactions after their separation. A previous study has
revealed that evolutionary breakpoints of chromosomes
show only intrachromosomal but not interchromosomal
3D proximity in the human nucleus (Véron et al. 2011).
Using high-resolution interchromosomal and intrachromosomal interaction data, we found that gene pairs that were
genomic neighbors in some yeast species, but are separated in
S. cerevisiae, show not only intrachromosomal but also interchromosomal colocalization in S. cerevisiae. This observation indicates that yeast-separated neighboring genes show
more widespread colocalization in the nucleus than humanseparated neighboring gene. This observation might be
explained by two possibilities: One is that recombination
might show a preference for rearrangements of genes to
their interchromosomal colocalized locus. Another possibility
is that if one gene is rearranged to a locus that shows no
interchromosomal colocalization with this gene, this locus
might be brought proximity to the locus where the gene
originally locates. It will be interesting to design an experiment
to test which is the main reason.
A key finding is that separated neighboring gene pairs
showing interchromosomal colocalization tend to be regulated by the same TF or histone modification. This property is
not dependent on separated neighboring gene pairs or interchromosomal colocalization alone, but the feature of separated neighboring gene pairs showing interchromosomal
colocalization. Based on these results, it is likely that TF coregulation and histone comodification constrain the nuclear
location of separated neighboring gene pairs, as nuclear colocalization might facilitate their coregulation and comodification. If this is the case, it will give insights into the evolutionary
roles of TF regulation and histone modification in shaping
nuclear gene location.
Materials and Methods
Gene order data of 17 yeast species were taken from the
YGOB version 7 (Byrne and Wolfe 2005). Using these data,
we searched for gene pairs that met two criteria: 1) The two
genes are on different chromosomes in S. cerevisiae.
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Dai et al. . doi:10.1093/molbev/msu065
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FIG. 3. Separated neighboring gene pairs showing interchromosomal colocalization tend to show similar transcription factor binding, similar histone
modification levels, and similar gene expression patterns. (A) Separated neighboring gene pairs showing interchromosomal colocalization tend to be
bound by the same transcription factor. (B) Separated neighboring gene pairs showing interchromosomal colocalization tend to have similar histone
modifications. Average values that correspond to absolute difference in histone modification levels between separated neighboring gene pairs are
shown for pairs showing interchromosomal colocalization and pairs not showing interchromosomal colocalization. (C) Average values that correspond
to histone modification levels are shown for separated neighboring gene pairs showing interchromosomal colocalization and the other genes.
(D) Separated neighboring gene pairs showing interchromosomal colocalization show gene coexpression. Average values that correspond to expression
Pearson correlation coefficient between separated neighboring gene pairs are shown for pairs showing interchromosomal colocalization and pairs not
showing interchromosomal colocalization. (E) Average values that correspond to expression Pearson correlation coefficient are shown for interchromosomal colocalized separated neighboring genes and their neighboring genes in Saccharomyces cerevisiae, and non-interchromosomal colocalized
separated neighboring genes and their neighboring genes in S. cerevisiae. Error bars in (B)–(E) were calculated by bootstrapping. The statistical significant
values calculated from Mann–Whitney U test are indicated.
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Interchromosomal Colocalization of Separated Neighboring Genes . doi:10.1093/molbev/msu065
2) The two genes are neighbor on the same chromosome in
at least one of the other 16 yeast species. These gene pairs are
referred to as separated neighboring gene pairs (11,693 pairs).
See supplementary materials, Supplementary Material online,
for more information on materials and methods.
Supplementary Material
Supplementary materials and methods, figures S1–S3, and
tables S1 and S2 are available at Molecular Biology and
Evolution online (http://www.mbe.oxfordjournals.org/).
Acknowledgments
The authors thank the two reviewers for helpful comments
and suggestions on the manuscript. This work was supported
by National Natural Science Foundation of China (NSFC)
(Grant 61202343), by Natural Science Foundation of
Guangdong Province (S2012040007935), and also by China
Postdoctoral Science Foundation funded project
(2013T60823).
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