Here, we investigated genome-wide relationship between gene regulation and gene location in the nucleus. Our major findings are that: (i) a considerable number of TFs show a preference to have targets that are colocalized in the nucleus; (ii) the colocalization of target genes strengthens coregulation of the corresponding TFs; and (iii) most chromatin regulators tend to regulate genes that are colocalized. These findings demonstrate the constraints of gene regulation on genome organization in the nucleus. These results have particular importance for studies attempting to understand gene regulation in the three-dimensional view. Future studies will no doubt need to take gene nuclear location into account in order to achieve a deeper understanding of gene regulation.
Our study provides genome-wide evidence for the colocalization of coregulated genes. A significant number of TFs regulate genes that are colocalized in the nucleus, but target genes of most TFs are not colocalized. It has become evident that the organization of chromatin in the nucleus is not static (50
). Examples of dynamic chromatin movements have been documented with regard to gene regulation (51
). On the other hand, it is well accepted that TFs bind their targets in a dynamic manner. Genes might dynamically move to specific nuclear regions for TF transient binding. Note that the three-dimensional map of yeast genome, we used for analysis represents an ‘average’ snapshot of genome organization in the nucleus, not the dynamic changes. It is likely that the dynamic colocalization of target genes for most TFs is not captured by this three-dimensional map. It is interesting to test this possibility with the development of experimental methods.
Transcription regulation is a TF-dependent process, and is achieved by the diffusion of TFs. TF regulatory efficiency is influenced by the protein abundance of TFs. If the abundance of one TF is high, it should efficiently regulate its target genes even though targets are scattered over the whole nuclear space. We hypothesized that nuclear colocalization of target-colocalized TF target genes is linked to the low TF abundance. However, we found that the abundance (26
) of target-colocalized TFs is comparable with that of the other TFs (P
0.67, Mann–Whitney U-test).
We sought to explain the nuclear colocalization of target genes in terms of the size of target gene cohorts. If one TF regulates a large number of genes, its appropriate regulation could be maintained by the colocalization of its target genes. The nuclear colocalization of target genes should enhance TF regulatory efficiency. However, the sizes of knockout target gene cohorts for target-colocalized TFs are comparable with those of the other TFs (96 versus 110; P
0.87, Mann–Whitney U-test).
TF target genes colocalized are in tighter coregulation by the TFs. TFs identify their target genes by binding the DNA motif sequences in promoter regions. TF binding DNA motifs are usually short and degenerate. There are thus, redundant motifs in the genome, which makes it difficult for TFs to appropriately bind their functional motifs. As gene expression data is measured among a population of cells, the failure of appropriate TF binding in a subpopulation of cells could lead to the apparently weak coregulation of TF target genes. In general, TFs are not randomly distributed in the nucleus, and they show a preference to locate in some distinct nuclear regions. Colocalization of TF target genes in these regions could facilitate the appropriate binding of TFs to function motifs, which strengthens the coregulation of TF target genes.
Histone modification and chromatin remodeling are known to be associated with transcription. It remains to be answered whether the colocalization of their gene cohorts facilitates transcription. We found that histone modifications whose gene cohorts are colocalized in the nucleus, show comparable correlation with transcription activity relative to the other histone modifications (P
0.15, Mann–Whitney U-test; Supplementary Figure S7
). Similar result was observed on chromatin remodeler target gene cohorts (P
0.49, Mann–Whitney U-test; Supplementary Figure S7
). These results indicate that chromatin regulators whose target genes show colocalization are not significantly associated with transcription activation or repression compared to the other regulators. Moreover, RNA polymerase II-enriched promoters are not colocalized in the nucleus (hypergeometric, P
1). The colocalization of target genes is a feature of some chromatin regulators, but it is not the general feature of chromatin regulators that are linked to transcription activation or repression. The colocalization might facilitate the regulation of chromatin regulators. Its functional roles in biological processes remain to be elucidated.
Our observation that genes coregulated by one chromatin regulator are colocalized has implications. Colocalized genes are regulated by common chromatin regulators. This could result in similar chromatin structures of colocalized genes. Our observation that genes with similar nucleosomal organization are colocalized, supports this concept. In addition, chromatin regulators could move their regulated genes to specialized compartments in the nucleus, leading to the observed colocalization of their coregulated genes. This will give insights into how colocalization of coregulated genes is accomplished.
Despite the findings described above, our study still has limitations. In this study, we used numerous data sets which are measured from different experimental platforms and different yeast strains (Supplementary Table S3
). These discrepancies inevitably bias the observations in this study. However, yeast data sets used in this study were all measured in rich media (Supplementary Table S3
). The similarity in experimental medium should complement the discrepancies above. It will be of particular interest to perform experiments regarding to this study using the same yeast strains.