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. 2008 Oct 14;105(41):15761-6.
doi: 10.1073/pnas.0806317105. Epub 2008 Oct 7.

Transcriptional regulation constrains the organization of genes on eukaryotic chromosomes

Sarath Chandra Janga  1 , Julio Collado-Vides, M Madan Babu
Affiliations

Transcriptional regulation constrains the organization of genes on eukaryotic chromosomes

Sarath Chandra Janga et al. Proc Natl Acad Sci U S A. .

Abstract

Genetic material in eukaryotes is tightly packaged in a hierarchical manner into multiple linear chromosomes within the nucleus. Although it is known that eukaryotic transcriptional regulation is complex and requires an intricate coordination of several molecular events both in space and time, whether the complexity of this process constrains genome organization is still unknown. Here, we present evidence for the existence of a higher-order organization of genes across and within chromosomes that is constrained by transcriptional regulation. In particular, we reveal that the target genes (TGs) of transcription factors (TFs) for the yeast, Saccharomyces cerevisiae, are encoded in a highly ordered manner both across and within the 16 chromosomes. We show that (i) the TGs of a majority of TFs show a strong preference to be encoded on specific chromosomes, (ii) the TGs of a significant number of TFs display a strong preference (or avoidance) to be encoded in regions containing particular chromosomal landmarks such as telomeres and centromeres, and (iii) the TGs of most TFs are positionally clustered within a chromosome. Our results demonstrate that specific organization of genes that allowed for efficient control of transcription within the nuclear space has been selected during evolution. We anticipate that uncovering such higher-order organization of genes in other eukaryotes will provide insights into nuclear architecture, and will have implications in genetic engineering experiments, gene therapy, and understanding disease conditions that involve chromosomal aberrations.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Schematic illustration showing the methods used to estimate the significance for chromosomal preference (A), regional preference (B), and clustering of target genes (C). See Materials and Methods for details. x, observed value; μ, mean; σ, standard deviation.
Fig. 2.
Fig. 2.
Chromosomal preference for binding by TFs. (A) Each column in the matrix represents one of the 16 chromosomes labeled I to XVI. Each row represents the Z score significance profile of a particular TF (shown on the right) to have its targets on the different chromosomes (see Fig. 1A). The top 75 TFs (selected by P value and higher Z scores) are ordered after hierarchically clustering their Z score profiles. The number of target genes is mentioned next to the gene name. (B) TFs with target preference for each of the 16 chromosomes. Only those TFs that show preference for binding to chromosomes with Z scores ≥ 3, P ≤ 10−3, and regulate >16 genes are shown. Each chromosome has a set of TFs that tend to preferentially bind them. The thickness of the red line is proportional to the absolute number of target genes for that TF on the chromosome. (C) Higher-order organization of regulatory interactions. The top column denotes the chromosomes where the TFs are encoded, and the bottom column denotes the chromosomes where the target genes are encoded. Red and blue lines connecting the two chromosomes mean that TFs originating from a specific chromosome tend to preferentially encode or avoid targets on a particular chromosome, respectively. The thickness is proportional to the Z score.
Fig. 3.
Fig. 3.
TFs showing significant regional preference or avoidance for binding on the chromosomes (see Fig. 1B). (A) TFs that show a strong tendency to have their targets on the C region, M region, or T region on the chromosome. (B) TFs that show a strong avoidance to have their targets on the three regions. Green boxes highlight the group of TFs that show significant regional avoidance for one of the three regions. In the diagram next to the matrices, thick black lines indicate preference and broken black lines indicate avoidance. Only TFs with P < 10−3 and |Z| ≥ 3 are shown in both cases. (C) Higher-order organization of regulatory interactions. The top column denotes regions on the chromosomal arm where the TFs are encoded and the bottom column denotes the regions where the targets are encoded. Lines connecting the two regions mean that TFs originating from a specific region tend to preferentially have (red lines) or avoid (blue lines) targets on a particular region of the chromosome. The thickness is proportional to the Z score.
Fig. 4.
Fig. 4.
Frequency distribution of TPI values. Distribution of Target Proximity Index (TPI) for all TFs in the real and randomly constructed networks at different proximity values, that is, D values (see Materials and Methods) are shown: (A) D ≤ 1 to D ≤ 5; (B) D ≤ 5 to D ≤ 30; and (C) D ≤ 40 to D ≤ 200. Note that, in the real network, the maximum proportion of TFs have TPI values that are much higher than what is seen for the random networks (at ≈0.8 for real network and 0.2 for random networks at D ≤ 20), demonstrating that most TFs show clustering of their targets in this distance range.
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