Transcriptional regulation constrains the organization of genes on eukaryotic chromosomes

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.gene order ͉ genome ͉ nuclear architecture ͉ systems biology ͉ network A lthough transcription in both prokaryotes and eukaryotes involves the evolutionarily conserved core RNA polymerase subunit, the whole process of transcriptional regulation is fundamentally different. In contrast to prokaryotes where transcription primarily relies on the cis-regulatory DNA sequences alone (1), eukaryotic transcription is regulated at least at three major levels (2, 3). The first is at the level of DNA sequence where the transcription factor (TF) associates with cis-regulatory elements to regulate transcription of the relevant gene (2). The second is at the level of chromatin, which allows segments within a chromosomal arm to switch between different transcriptional states, that is, between a state that suppresses transcription and one that allows for gene activation (2). This involves changes in nucleosome occupancy and chromatin structure, both of which are controlled by the interplay between remodeling complexes, histone modification, DNA methylation, and a variety of repressive and activating mechanisms (4, 5). The third is at the level of nuclear architecture, which includes organization of chromosomes into chromosomal territories, and the dynamic, temporal, and spatial organization of specific chromosomal loci-all of which are known to influence gene expression (6-11). Thus, unlike in prokaryotes, transcription in eukaryotes is an energy-intensive, multi...

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