Gene coexpression domains in the human genome

Prokaryotic operons normally comprise functionally related genes whose expression is coordinated. Even though operons do not exist in most eukaryotes, results from the last fifteen years indicate that gene order is nonetheless not random in eukaryotes. 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. Using human normal breast and breast cancer RNA-seq data, we identify approximately 500 coexpression domains (which we term “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 topologically associating domains (TADs). However, the chromatin 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 3D contacts which could be related to looping to the same enhancers or a consequence of being transcribed in the same “transcription factories”.