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Transcriptional Regulation Constrains the Organization of Genes on Eukaryotic Chromosomes

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Transcriptional Regulation Constrains the Organization of Genes on Eukaryotic Chromosomes Transcriptional regulation constrains the organization of genes on eukaryotic chromosomes Sarath Chandra Janga*†, Julio Collado-Vides‡, and M. Madan Babu*† *Laboratory of Molecular Biology, Medical Research Council, Hills Road, Cambridge CB2 0QH, United Kingdom; and ‡Programa de Genomica Computacional, Centro de Ciencias Genomicas, Universidad Nacional Autonoma de Mexico, Apartado Postal 565-A, Av Universidad, Cuernavaca, Morelos, 62100 Mexico D.F., Mexico Edited by Aaron Klug, Medical Research Council, Cambridge, United Kingdom, and approved August 21, 2008 (received for review July 1, 2008) Genetic material in eukaryotes is tightly packaged in a hierarchical organization of genes across the different eukaryotic chromosomes. manner into multiple linear chromosomes within the nucleus. This becomes particularly interesting in the light of a recent work Although it is known that eukaryotic transcriptional regulation is that demonstrated that tuning the expression level of a single gene complex and requires an intricate coordination of several molec- could provide an enormous fitness advantage to an individual in a ular events both in space and time, whether the complexity of this population of cells (12). Thus, one could extrapolate that optimi- process constrains genome organization is still unknown. Here, we zation of transcriptional regulation on a global scale, such as the present evidence for the existence of a higher-order organization efficient expression of relevant genes under specific conditions, of genes across and within chromosomes that is constrained by would have significant advantage on the fitness of an individual in transcriptional regulation. In particular, we reveal that the target a genetically heterogeneous population. genes (TGs) of transcription factors (TFs) for the yeast, Saccharo- Although several studies have reported that genes with similar myces cerevisiae, are encoded in a highly ordered manner both expression patterns cluster on the genome and that gene order is across and within the 16 chromosomes. We show that (i) the TGs conserved, no study has investigated whether transcriptional reg- of a majority of TFs show a strong preference to be encoded on ulation has constrained organization of genes across and within the specific chromosomes, (ii) the TGs of a significant number of TFs chromosomes; in particular, whether the set of genes regulated by display a strong preference (or avoidance) to be encoded in regions a given TF are (i) randomly distributed across different chromo- containing particular chromosomal landmarks such as telomeres somes or encoded on specific chromosomes, (ii) distributed in an and centromeres, and (iii) the TGs of most TFs are positionally unbiased manner within a chromosomal arm or display preference clustered within a chromosome. Our results demonstrate that to be encoded in regions containing particular chromosomal land- specific organization of genes that allowed for efficient control of marks, or (iii) positionally clustered within a chromosome. Here, we transcription within the nuclear space has been selected during investigate these questions by using the recently available genome- evolution. We anticipate that uncovering such higher-order orga- scale data on 13,853 high-confidence regulatory interactions (Fig. nization of genes in other eukaryotes will provide insights into S1). These data cover 156 TFs and 4,495 target genes for the model nuclear architecture, and will have implications in genetic engi- eukaryote Saccharomyces cerevisiae, whose genetic material is or- neering experiments, gene therapy, and understanding disease ganized into 16 linear chromosomes. conditions that involve chromosomal aberrations. Results and Discussion gene order ͉ genome ͉ nuclear architecture ͉ systems biology ͉ network The Majority of TFs Show a Strong Preference to Regulate Genes on Specific Chromosomes. Several elegant studies have elucidated that lthough transcription in both prokaryotes and eukaryotes the organization of chromosomes within the eukaryotic nucleus is Ainvolves the evolutionarily conserved core RNA polymerase nonrandom and that they occupy distinct volumes called chromo- subunit, the whole process of transcriptional regulation is funda- somal territories (6, 7). In yeast, in addition to the ordered move- mentally different. In contrast to prokaryotes where transcription ments during cell division, it has been demonstrated that interphase chromosomes undergo large rapid movements (Ͼ0.5 ␮m in a 10-s primarily relies on the cis-regulatory DNA sequences alone (1), Ϸ ␮ eukaryotic transcription is regulated at least at three major levels (2, interval; nuclear diameter of 2 m) and that such movements 3). The first is at the level of DNA sequence where the transcription could reflect the metabolic state of the cell (Fig. S1; refs. 7 and 9 factor (TF) associates with cis-regulatory elements to regulate and references therein). These observations have suggested that the transcription of the relevant gene (2). The second is at the level of nonrandom organization of the chromosomes could (i) allow chromatin, which allows segments within a chromosomal arm to functional compartmentalization of the nuclear space, thus poten- switch between different transcriptional states, that is, between a tially enhancing or repressing expression of specific genes, and (ii) state that suppresses transcription and one that allows for gene bring coregulated genes into physical proximity to coordinate gene activation (2). This involves changes in nucleosome occupancy and expression. The above-mentioned observations on the nonrandom chromatin structure, both of which are controlled by the interplay nuclear architecture and chromosomal dynamics together with the between remodeling complexes, histone modification, DNA meth- fact that transcriptional regulation in eukaryotes is an energy- ylation, and a variety of repressive and activating mechanisms (4, 5). The third is at the level of nuclear architecture, which includes Author contributions: S.C.J. and M.M.B. designed research; S.C.J. and M.M.B. performed organization of chromosomes into chromosomal territories, and the research; J.C.-V. contributed new reagents/analytic tools; S.C.J. and M.M.B. analyzed data; dynamic, temporal, and spatial organization of specific chromo- and S.C.J. and M.M.B. wrote the paper. somal loci–all of which are known to influence gene expression The authors declare no conflict of interest. (6–11). Thus, unlike in prokaryotes, transcription in eukaryotes is This article is a PNAS Direct Submission. an energy-intensive, multistep process, involving a large number of Freely available online through the PNAS open access option. molecular events to be coordinated both in space and time [sup- †To whom correspondence may be addressed. E-mail: [email protected] or porting information (SI) Fig. S1]. Given the intricacy involved in a [email protected] single transcriptional regulatory interaction, one can ask whether or This article contains supporting information online at www.pnas.org/cgi/content/full/ BIOPHYSICS not the complexity of the whole network of transcriptional inter- 0806317105/DCSupplemental. actions (Fig. S1) has imposed a significant constraint on the © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0806317105 PNAS ͉ October 14, 2008 ͉ vol. 105 ͉ no. 41 ͉ 15761–15766 Downloaded by guest on September 26, 2021 Step 1 Step 2 Step 3 A Transcription factor Chr1 Chr2 Chr3 Chr16 Observed: 4 2 0 … 5 Chr1 Chr2 Chr3 Chr16 Chromosomal (11 targets across 3 chromosomes) Z-score profile: +5+1 -1 … +7 preference Expected: 111… 1 Do transcription factors x - µ The TF preferentially binds preferentially regulate . Z-score = Chr1 Chr2 Chr16 σ to chromosomes 1 and 16 genes on specific chromosomes? Obtain the expected occurrence Obtain the number of binding events profile by analyzing 1000 Obtain the Z-score profile and for a TF on the different randomly rewired networks and identify TFs that show chromosomal chromosomes, i.e. occurrence profile calculate Z-scores affinity (i.e. Z-score ≥ 3) Step 1 Step 2 Step 3 B T-region CMT Regional TF (11 targets in 2 CMT M-region 4 0 Z-score chromosomes) Observed: 0 +7 -2 -1 preference C-region profile: Expected: 121 Do transcription factors C-region preferentially bind or avoid . M-region x - µ The TF preferentially binds to Z-score = specific regions on the Chr1 Chr2 T-region σ regions close to the centromere chromosomes? (i.e. the centromeric, middle or Obtain the number of binding events Obtain the expected occurrence Obtain the Z-score profile and telomeric region) on the different regions of the profile by analyzing 1000 chromosome (centromeric, middle, randomly rewired networks and identify TFs that show regional telomeric) and get occurrence profile calculate Z-scores preference (i.e. Z-score ≥ 3) Step 1 Step 3 Step 2 C TPI = TPI Transcription factor C C=8 N Clustering of (11 targets across 3 chromosomes) Observed: .72 targets Z-score +8 Expected: .12 Fig. 1. Schematic illustration N=11 Do transcription factors showing the methods used to esti- preferentially regulate The TF has targets that are . mate the significance for chromo- genes that are proximal preferentially clustered on Chr1 Chr2 Chr16 Create a network where nodes are somal preference (A), regional pref- on a chromosome? the chromosome targets and link genes if they are erence (B), and clustering of target Obtain the number (N) and position separated by ≤ 10 genes. Identify
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