The regulation of gene expression is a fundamental process within every cell that often allows exquisite control over a gene's activity (for review see [1
]). Altering transcription rates is an effective strategy for regulating gene activity. It is well established that transcription of a given gene is dependent upon a promoter sequence located within a few hundred base pairs of the transcriptional start site. Promoter activity is modulated by sequence-specific transcription factors that physically interact either with the protein complexes that make up the core transcriptional machinery or with the promoter sequence itself.
In eukaryotes, the activity of a promoter can be modified by transcription factors binding to DNA sequences (frequently termed cis-regulatory modules or enhancers) that are located from hundreds to hundreds of thousands of base pairs away from the promoter. These regulatory modules can either increase or decrease the rate of transcription for a target gene, depending on the cellular state and the activities of the bound transcription factors. There are several mechanisms by which transcription factors bound to regulatory modules exert their effects. First, many transcription factors interact directly with the core transcriptional machinery by recruiting the latter's protein complexes to the promoter. Second, transcription factors may bend or twist the DNA, altering the way in which other transcription factors interact with the DNA. Finally, transcription factors can alter local chromatin structure by modifying histones (typically through methylation, acetylation, and substitution of histone subunits) to permit or restrict access to the DNA. Modifications of chromosome structure also occur at much larger scales. Most eukaryotes exhibit distinct chromosomal regions that are usually either transcriptionally active (euchromatin) or inactive (heterochromatin). In animals, heterochromatin is typically found near centromeres and other regions of low sequence complexity.
Less clear are the mechanisms by which the regulation provided by a cis
-regulatory module is restricted to specific target genes. Several examples of insulators - sequences that prevent neighboring modules from affecting transcription - have been identified (reviewed in [2
]). Insulators seem to function not by deactivating cis
-regulatory modules but by preventing their influence from being propagated along the chromosome. It is not known how common insulators are in the Drosophila
(or any other) genome. Some insulator-binding proteins localize to a few hundred chromosomal positions, and these positions coincide with genomic sequences that are not heavily compacted by chromatin structure (the 'interbands' of polytene chromosomes) [3
]. There is substantial evidence that, although gene expression can be tightly controlled, neighboring genes or chromatin regions are important for the expression of individual genes. For example, otherwise identical transgenes inserted into different chromosomal sites show varying levels of expression [4
Two recent observations lend credence to the idea that genomes may be divided into domains important for controlling the expression of groups of adjacent genes. First, there is evidence from budding yeast that some genes are found in pairs or triplets of adjacent genes that display similar expression patterns [5
]. Second, about 50 much larger regions of the human genome show a strong clustering of highly expressed genes [6
], which is caused by clustering of genes that are expressed in nearly all tissues [7
]. We have examined the fraction of genes in the Drosophila
genome that are subject to regulation that reflects large domains, using data from high-density oligonucleotide microarrays that reflect over 80 experimental conditions, and have found more than 20% of the genes clustered into co-regulated groups of 10-30 genes.