Abstract
Gene order is not random in eukaryotic chromosomes, and co-regulated genes tend to be clustered. The mechanisms that determine co-regulation of large regions of the genome and its connection with chromatin three-dimensional (3D) organization are still unclear however. Here we have adapted a recently described method for identifying chromatin topologically associating domains (TADs) to identify coexpression domains (which we term “CODs”). Using human normal breast and breast cancer RNA-seq data, we have identified approximately 500 CODs. CODs in the normal and breast cancer genomes share similar characteristics but differ in their gene composition. COD genes have a greater tendency to be coexpressed with genes that reside in other CODs than with non-COD genes. Such inter-COD coexpression is maintained over large chromosomal distances in the normal genome but is partially lost in the cancer genome. Analyzing the relationship between CODs and chromatin 3D organization using Hi-C contact data, we find that CODs do not correspond to TADs. In fact, intra-TAD gene coexpression is the same as random for most chromosomes. However, the contact profile is similar between gene pairs that reside either in the same COD or in coexpressed CODs. These data indicate that co-regulated genes in the genome present similar patterns of contacts irrespective of the frequency of physical chromatin contacts between them.
Highlights
Genome-wide expression studies have shown that gene order is not random in eukaryotes, and that genes with similar expression patterns are often linked
Even though operons do not exist in most eukaryotes, results from the last fifteen years indicate that gene order is not random in eukaryotes, and that coexpressed genes tend to be grouped in the genome
We identify here about 500 coexpression domain (CODs) in normal breast tissue
Summary
Genome-wide expression studies have shown that gene order is not random in eukaryotes, and that genes with similar expression patterns are often linked (reviewed in [1, 2]). Clusters of genes with similar expression patterns and related functions have been identified in several model organisms. Muscle expressed genes have been shown to cluster in Caenorhabditis elegans [5] and in humans [6]. Clustering of other tissue-specific genes has been reported in Drosophila [7], mouse [8, 9], and human [10, 11]. Lee and Sonnhameer showed that genes involved in the same KEGG pathway tend to be clustered in several eukaryotic genomes [12]. Clusters of housekeeping genes [18] or of highly expressed genes [19] have been reported
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