Chromosomal clustering of a human transcriptome reveals regulatory background

Abstract

Background: There has been much evidence recently for a link between transcriptional regulation and chromosomal gene order, but the relationship between genomic organization, regulation and gene function in higher eukaryotes remains to be precisely defined.

Results: Here, we present evidence for organization of a large proportion of a human transcriptome into gene clusters throughout the genome, which are partly regulated by the same transcription factors, share biological functions and are characterized by non-housekeeping genes. This analysis was based on the cardiac transcriptome identified by our genome-wide array analysis of 55 human heart samples. We found 37% of these genes to be arranged mainly in adjacent pairs or triplets. A significant number of pairs of adjacent genes are putatively regulated by common transcription factors (p = 0.02). Furthermore, these gene pairs share a significant number of GO functional classification terms. We show that the human cardiac transcriptome is organized into many small clusters across the whole genome, rather than being concentrated in a few larger clusters.

Conclusion: Our findings suggest that genes expressed in concert are organized in a linear arrangement for coordinated regulation. Determining the relationship between gene arrangement, regulation and nuclear organization as well as gene function will have broad biological implications.

Figure 1

Gene localization based on Ensembl, HU2 and HXP. Genes marked with * illustrate an adjacent gene pair in reference to HU2 and HXP, but not referring to the Ensembl gene set (131 cases). Therefore, only genes like those marked with # are noted as clusters throughout.

Figure 2

Genomic organization of the overall and clustered heart-expressed genes. The chromosomal gene order of clustered genes is represented in red, whereas the non-clustered genes are shown in gray, both appear to distribute without notable prevalence among the chromosomes.

Figure 3

Tissue expression of overall and clustered HXP genes. The numbers of tissue expression of clustered heart-expressed genes are presented filled black. Of the 79 analyzed tissues, the expression profile of clustered genes shows a broad panel of tissue expression but only very few clustered genes are expressed in the majority of tissues. Thus we concluded that clustered coexpressed genes are mainly non-housekeeping genes.

Figure 4

Example of four adjacent coexpressed genes. Shown is the gene cluster distribution on human chromosome 2 with an example of four adjacent genes regulated in part by common transcription factors and sharing gene ontology categories. Coexpressed gene clusters are shown in red. Each coexpressed gene pair ABI2 – RAPH1; RAPH1 – CD28 and CD28 – CTLA4 shares GO terms as indicated. Genes of the triplet RAPH1 – CD28 – CTLA4 have transcription factor binding sites for AP3 and EV1 in common. Furthermore, each gene pair RAPH1 – CD28 and CD28 – CTLA4 shares additional TFBS. Genes are marked in green, arrows indicate the strand orientation, promotor regions and transcription factors are colored in yellow.