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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 ß The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: [email protected] 1166 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 MBE 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 1167 Dai et al. . doi:10.1093/molbev/msu065 MBE 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 1168 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 MBE 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. 1169 Dai et al. . doi:10.1093/molbev/msu065 MBE 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. 1170 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. 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