A Non-Random Walk Through the Genome Comment Brian Oliver* and Tom Misteli†

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A Non-Random Walk Through the Genome Comment Brian Oliver* and Tom Misteli† Review A non-random walk through the genome comment Brian Oliver* and Tom Misteli† Addresses: *National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. †National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. Correspondence: Brian Oliver. E-mail: [email protected]. Tom Misteli. E-mail: [email protected] reviews Published: 31 March 2005 Genome Biology 2005, 6:214 (doi:10.1186/gb-2005-6-4-214) The electronic version of this article is the complete one and can be found online at http://genomebiology.com/2005/6/4/214 © 2005 BioMed Central Ltd reports Abstract Recent publications on a wide range of eukaryotes indicate that genes showing particular expression patterns are not randomly distributed in the genome but are clustered into contiguous regions that we call neighborhoods. It seems probable that this organization is related to chromatin and the structure of the nucleus. deposited research Consideration of gene regulation as an interaction between the lingering questions about the best methods for finding them basal transcription machinery, regulators, and a segment of and about how to avoid being tricked by spurious or artifac- naked DNA containing a gene has been an extremely successful tual patterns, the body of available evidence leaves little model for understanding how genetic information is read [1]. It doubt that they exist. With a few exceptions from classical is impossible to separate this model from the great success of molecular biology, the regulatory mechanisms underlying modern molecular genetics. Naked DNA does not exist in gene-expression neighborhoods are not understood. Investi- refereed research nature, however. Packing DNA into the nucleus, segregating it gating these mechanisms will be a major challenge, but we during cell division, and making sure that it is readily available believe that some will involve the structure of the nucleus. We when needed for transcription is an enormously complex task review the evidence for non-random positioning of chromo- for the cell and needs extensive interactions of proteins with somes and genes in the nucleus and suggest ways in which DNA. Structural considerations have dominated our views of the regulation of gene-expression neighborhoods can be nuclear architecture but have not greatly influenced our con- studied. cepts of transcription, other than by the broad assumption that such structure can hinder transcription. As with a building, interactions however, the structure of the nucleus has a significant, albeit Evidence for gene-expression neighborhoods possibly subtle, influence on the work performed within it. It has long been known that prokaryotic genes are organized into operons [2]. Even in eukaryotes, it has been recognized Recent work in many different eukaryotes has suggested that that some genes encoding related functions are near neighbors genes with particular expression patterns are sometimes in the genome: the clusters of genes encoding histones and found in contiguous regions of the genome. We call these tRNAs and the arrays of ribosomal RNA (rRNA) genes were regions gene-expression neighborhoods; we avoid using the early examples [3]. Although the lists of known gene neighbor- term ‘cluster’ because this usually refers to potentially co- hoods like these have grown and now include important regu- information regulated genes, regardless of their genomic position. The latory genes such as the Hox and microRNA genes [4,5], most human eye is exceedingly adept at finding patterns and does researchers have considered gene neighborhoods oddities. so even in randomness (the constellations of stars are an example of patterns that humans have imposed on a random There have been hints that gene-expression neighborhoods are distribution). Here, we review the evidence that gene- widespread. For example, direct examination of Drosophila expression neighborhoods are real. Although there are some polytene chromosomes showed nascent transcripts being Genome Biology 2005, 6:214 214.2 Genome Biology 2005, Volume 6, Issue 4, Article 214 Oliver and Misteli http://genomebiology.com/2005/6/4/214 generated from many genes in some multigene segments [6], (a) and the systematic analysis of the effect of position on trans- High Low Males Testis gene expression supported the idea that there are regions, Samples CG ID Name CG1162 BG:DS00276.8 both euchromatic and heterochromatic, that are broadly CG1034 bcd CG1034 bcd repressive [7]. Functional assays like these, in conjunction CG2198 Ama CG2189 Dfd CG1030 Scr with structural studies, raise the possibility that loop CG2047 ftz CG1028 Antp domains within chromosomes (the domains between CG1982 Sodh-1 CG1979 BG:DS00464.1 matrix-attachment regions) are units of transcriptional regu- CG1980 dj CG1984 CG1984 lation [8]. Genome-scale analyses of gene expression using CG1988 CG1988 CG1105 CG1105 microarrays have resulted in an explosion of papers describing CG1965 CG1965 CG1104 CG1104 CG1943 CG1943 gene-expression neighborhoods. Non-random expression of CG1943 CG1943 CG1101 Aly pairs of adjacent genes has been reported in yeast [9] and Genes in order along the chromosome CG1939 CG1939 plants [10], and among highly expressed human genes [11], (b) genes expressed in Caenorhabditis elegans muscle [12], genes differentially expressed in embryonic versus adult Drosophila [13,14], genes differing in expression between the sexes [15,16], and genes expressed in cancerous cells [17]. Chr 15 There are a number of pitfalls to the analysis of neighbor- hoods of contiguous genes, calling for great analytical rigor. Chr 12 For example, the position of the elements on the array must be taken into account, as non-random hybridization across DNA the array landscape is often significant: for example, some early arrays had probes printed in the same order as they appear in the genome [18]. But expression data generated using arrays with probes printed randomly with respect to chromosome position, analyzed under very stringent criteria Figure 1 An illustration of gene neighborhoods and chromosome territories. comparing real data to 100,000 random sets, still show (a) A heat diagram showing normalized hybridization intensities along a gene-expression neighborhoods (an example from our own segment of a Drosophila chromosome. Samples are arrayed from left to analyses on Drosophila [16] is shown in Figure 1a). Findings right, and samples from testis and males (including testis) are indicated; of such non-random patterns are also independent of the genes that are adjacent on chromosome 3R are listed from top to bottom. Four contiguous genes, including the don juan gene (dj) that technique used. Sequencing-based assays such as expressed encodes a sperm tail protein, show testis-biased and male-biased sequence tags (ESTs) and serial analysis of gene expression expression. Figure generated using data from [16]. (b) A micrograph of (SAGE) are not subject to array artifacts of any kind; experi- liver cells, showing the positions that two chromosomes preferentially ments using these techniques have shown in mammals that occupy within the nucleus. Chromosome 12 (green) is frequently found towards the periphery, whereas chromosome 15 (red) tends to localize highly expressed genes [19] and genes with testis-biased towards the center of the nucleus. Blue indicates total DNA staining. [20] or organ-biased [21] expression are organized into neighborhoods. Finally, a computational analysis of the gene correlation between gene location and inferred gene func- tion in many eukaryotes shows neighborhood structure [19]. within the blocks of the Drosophila melanogaster genome that are conserved with Drosophila pseudoobscura is highly The fact that genes can be moved to new locations in the correlated, suggesting that neighborhood structure is gener- genome and often behave more or less as expected in the ally conserved [15]. new location suggests that the effects of neighborhoods on gene expression are subtle. But subtle is not synonymous with unimportant. Reverse-genetic studies have shown that Non-random positioning of chromosomes in many genes have little overt phenotype when mutated or the nucleus deleted - usually because of redundancy with other genes - In the interphase nucleus of virtually all eukaryotes, the but even such apparently redundant duplicated genes cannot genetic material of each chromosome occupies a spatially last through evolutionary timescales without evolving func- limited, roughly spherical volume, with a diameter about a tions that differentiate them from other genes [22]. Our tenth of that of the nucleus, referred to as a chromosome ter- inability to assay small differences in fitness limits the identi- ritory [24,25] (Figure 1b). Despite the homogeneous dense fication of subtle effects. Conservation of neighborhood struc- appearance of these territories when visualized by in situ ture over a long evolutionary history, as seen for the Hox hybridization methods, their interiors are accessible to regu- genes [4] and in prokaryotic genomes [23], is a very powerful latory factors, and they are open enough to allow transport indicator that neighborhoods are functional. Gene expression of mRNA and proteins through the nucleus. Chromosome Genome Biology 2005, 6:214 http://genomebiology.com/2005/6/4/214 Genome Biology 2005, Volume 6, Issue 4, Article 214 Oliver and Misteli
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