Increasing alternative promoter repertories is positively associated with differential expression and disease susceptibility

Abstract

Background: Alternative Promoter (AP) usages have been shown to enable diversified transcriptional regulation of individual gene in a context-specific (e.g., pathway, cell lineage, tissue type, and development stage et. ac.) way. Aberrant uses of APs have been directly linked to mechanism of certain human diseases. However, whether or not there exists a general link between a gene's AP repertoire and its expression diversity is currently unknown. The general relation between a gene's AP repertoire and its disease susceptibility also remains largely unexplored.

Methodology/principal findings: Based on the differential expression ratio inferred from all human microarray data in NCBI GEO and the list of disease genes curated in public repositories, we systemically analyzed the general relation of AP repertoire with expression diversity and disease susceptibility. We found that genes with APs are more likely to be differentially expressed and/or disease associated than those with Single Promoter (SP), and genes with more APs are more likely differentially expressed and disease susceptible than those with less APs. Further analysis showed that genes with increased number of APs tend to have increased length in all aspects of gene structure including 3' UTR, be associated with increased duplicability, and have increased connectivity in protein-protein interaction network.

Conclusions: Our genome-wide analysis provided evidences that increasing alternative promoter repertories is positively associated with differential expression and disease susceptibility.

Figure 1. Distribution of differential expression ratio for each gene class.

The figure (density plot) showed that genes with more alternative promoters are more likely to be differentially expressed. SP means gene with single promoter, while AP = 2, AP = 3∼4, and AP> = 5 means gene with only 2 promoters, 3 or 4 promoters, and at least 5 promoters, respectively.

Figure 2. Fraction of cancer driver genes for each gene class.

The figure showed that genes with more alternative promoters tend to be enriched with cancer driver gene. The Y-axis is the fraction of genes belonging to cancer driver gene in each gene class. SP means gene with single promoter while AP means gene with alternative promoters. AP = 2, AP = 3∼4, and AP> = 5 means gene with only 2 promoters, 3 or 4 promoters, and at least 5 promoters, respectively.

Figure 3. Fraction of disease genes for each gene class.

The figure showed that genes with more alternative promoters tend to be enriched with disease gene. The Y-axis is the fraction of genes belonging to disease gene in each gene class. SP means gene with single promoter while AP means gene with alternative promoters. AP = 2, AP = 3∼4, and AP> = 5 means gene with only 2 promoters, 3 or 4 promoters, and at least 5 promoters, respectively.

Figure 4. Length distribution for the 3′ un-translated region (3′ UTR) of each gene class.

The figure (density plot) showed that genes with more alternative promoters tend to have longer 3′ UTR. SP means gene with single promoter, while AP = 2, AP = 3∼4, and AP> = 5 means gene with only 2 promoters, 3 or 4 promoters, and at least 5 promoters, respectively.

Figure 5. Fraction of duplicate genes for each gene class.

The figure showed that genes with more alternative promoters tend to have increased duplicability. The Y-axis is the fraction of genes belonging to duplicate gene in each gene class. SP means gene with single promoter while AP means gene with alternative promoters. AP = 2, AP = 3∼4, and AP> = 5 means gene with only 2 promoters, 3 or 4 promoters, and at least 5 promoters, respectively.

Figure 6. Distribution of node connectivity (degree) for each gene class in human protein-protein interaction network.

The figure (density plot) showed that genes with more alternative promoters tend to have increased node connectivity. SP means gene with single promoter, while AP = 2, AP = 3∼4, and AP> = 5 means gene with only 2 promoters, 3 or 4 promoters, and at least 5 promoters, respectively.