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. 2008 Dec 23:9:628.
doi: 10.1186/1471-2164-9-628.

Human and mouse switch-like genes share common transcriptional regulatory mechanisms for bimodality

Adam Ertel  1 , Aydin Tozeren
Affiliations

Human and mouse switch-like genes share common transcriptional regulatory mechanisms for bimodality

Adam Ertel et al. BMC Genomics. .

Abstract

Background: Gene expression is controlled over a wide range at the transcript level through complex interplay between DNA and regulatory proteins, resulting in profiles of gene expression that can be represented as normal, graded, and bimodal (switch-like) distributions. We have previously performed genome-scale identification and annotation of genes with switch-like expression at the transcript level in mouse, using large microarray datasets for healthy tissue, in order to study the cellular pathways and regulatory mechanisms involving this class of genes. We showed that a large population of bimodal mouse genes encoding for cell membrane and extracellular matrix proteins is involved in communication pathways. This study expands on previous results by annotating human bimodal genes, investigating their correspondence to bimodality in mouse orthologs and exploring possible regulatory mechanisms that contribute to bimodality in gene expression in human and mouse.

Results: Fourteen percent of the human genes on the HGU133A array (1847 out of 13076) were identified as bimodal or switch-like. More than 40% were found to have bimodal mouse orthologs. KEGG pathways enriched for bimodal genes included ECM-receptor interaction, focal adhesion, and tight junction, showing strong similarity to the results obtained in mouse. Tissue-specific modes of expression of bimodal genes among brain, heart, and skeletal muscle were common between human and mouse. Promoter analysis revealed a higher than average number of transcription start sites per gene within the set of bimodal genes. Moreover, the bimodal gene set had differentially methylated histones compared to the set of the remaining genes in the genome.

Conclusion: The fact that bimodal genes were enriched within the cell membrane and extracellular environment make these genes as candidates for biomarkers for tissue specificity. The commonality of the important roles bimodal genes play in tissue differentiation in both the human and mouse indicates the potential value of mouse data in providing context for human tissue studies. The regulation motifs enriched in the bimodal gene set (TATA boxes, alternative promoters, methlyation) have known associations with complex diseases, such as cancer, providing further potential for the use of bimodal genes in studying the molecular basis of disease.

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Figures

Figure 1
Figure 1
ECM-receptor interaction pathway enriched by human switch-like genes. Nodes enriched for human bimodal genes are colored orange, while nodes also identified as bimodal in mouse orthologs are outlined in bold. In all, the overlap between bimodal human and bimodal mouse orthologs contains thirteen unique genes represented in seven unique nodes in the ECM-receptor pathway. Nodes colored in gray were not identified as bimodal, while white nodes are used for genes that are not represented on the HGU133A array.
Figure 2
Figure 2
KEGG Focal adhesion pathway enriched by human switch-like genes. Nodes enriched for human bimodal genes are colored orange, while nodes also identified as bimodal in mouse orthologs are outlined in bold. In all, the overlap between human and mouse orthologs contains twenty-two unique genes represented in nine unique nodes in the focal adhesion pathway. Nodes colored in gray were not identified as bimodal, while white nodes are used for genes that are not represented on the HGU133A array.
Figure 3
Figure 3
Summary of promoter usage between bimodal and non-bimodal subsets. The relative frequency of core promoter types cataloged in MPromDB [13] is shown for bimodal and non-bimodal gene subsets in A) human and B) mouse. The number of alternative promoters per gene is shown for bimodal genes and non-bimodal genes for C) human and D) mouse. For a subset of bimodal genes with multiple alternative promoters, tissue-dependent alternative promoters from DBTSS [14] corresponded to the mode of expression, as shown for glutamate receptors E) GRIA2 in human and F) Gria1 in mouse.
Figure 4
Figure 4
Bimodal gene enrichment for promoter region methylation of lysine 4 of histone H3 (H3K4me3). A) Fraction of bimodal vs. non-bimodal genes enriched for histone methylation within their promoters as reported by Guenther et al. [12] for H9 hES cells, liver (hepatocytes), and B-cells. The fourth and fifth sets of bars represent the set of genes enriched at high confidence within one tissue but not the other liver versus hES cells and B-cell versus hES cells. B) H3K4me3 enrichment ratio from Guenther et al. [12] for liver vs. stem cells is shown for bimodal genes. Genes expressed with "high" mode in liver and "low" mode in H9 stem cells are shown with green "+" symbols, while bimodal genes expressed with "low" mode in liver and "high" mode in stem cells are shown with blue "x" symbols. Black points are used for the remaining bimodal genes expressed in common modes between these two tissue types. The standard deviation around the line y = x (solid red line) is shown as dashed red lines.
Figure 5
Figure 5
Bimodal gene expression. The histogram and normal mixture probability density function (pdf) are shown for a typical bimodal gene. The threshold between the high and low mode of expression is labeled as XT and darker shading is used to represent the misclassification region.
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