PEREGRINE: A genome-wide prediction of enhancer to gene relationships supported by experimental evidence

Abstract

Enhancers are powerful and versatile agents of cell-type specific gene regulation, which are thought to play key roles in human disease. Enhancers are short DNA elements that function primarily as clusters of transcription factor binding sites that are spatially coordinated to regulate expression of one or more specific target genes. These regulatory connections between enhancers and target genes can therefore be characterized as enhancer-gene links that can affect development, disease, and homeostatic cellular processes. Despite their implication in disease and the establishment of cell identity during development, most enhancer-gene links remain unknown. Here we introduce a new, publicly accessible database of predicted enhancer-gene links, PEREGRINE. The PEREGRINE human enhancer-gene links interactive web interface incorporates publicly available experimental data from ChIA-PET, eQTL, and Hi-C assays across 78 cell and tissue types to link 449,627 enhancers to 17,643 protein-coding genes. These enhancer-gene links are made available through the new Enhancer module of the PANTHER database and website where the user may easily access the evidence for each enhancer-gene link, as well as query by target gene and enhancer location.

Fig 1. The number of enhancer-gene links found in each assay.

This Venn diagram (not to scale) shows the number of enhancer gene-links found in each assay and each combination of assays.

Fig 2. Distributions of enhancer-gene links.

A. The distribution of the number of putative target genes for each enhancer. Each bar represents the quantity of enhancers with each given value of linked genes. B. The distribution of the number of enhancers linked to each gene. Each bar represents the quantity of genes with each given value of linked enhancers. C. The distribution of the number of total tissues each enhancer-gene link was found in. Each bar represents the quantity of enhancer-gene links with each given value of tissues giving supporting evidence of the link.

Fig 3. Clustering of genes enriched among PEREGRINE enhancer-gene links as being linked to fewer enhancers than expected.

A. Genes with function related to immune system processes shown to cluster. B. Olfactory receptors on chromosome 14 annotated with as part of the GO biological process “detection of chemical stimulus involved in sensory perception of smell” GO:0050911 (p<1.0E-10). C. Olfactory receptors on chromosome 17 annotated with as part of the GO biological process “detection of chemical stimulus involved in sensory perception of smell” GO:0050911 (p<1.0E-10). D. Taste receptors on chromosome 7 annotated with as part of the GO biological process “detection of chemical stimulus involved in sensory perception of taste” GO:0050912 (p<1.0E-10). E. Taste receptors on chromosome 12 annotated with as part of the GO biological process “detection of chemical stimulus involved in sensory perception of taste” GO:0050912 (p<1.0E-10) F. Enrichment analysis for GO biological processes based on number of enhancers linked to each gene.

Fig 4. Viewing enhancer-gene link information on a gene list.

The PANTHER website is able to take a list of genes from the user and provide a list of enhancers associated with each gene presented as a hyperlink to more information about the supporting evidence for each enhancer-gene link as well as its cell and tissue type. (Screenshot of the PANTHER website⁴⁵ published under CC BY license with permission from the original copyright holder).

Fig 5. The schema of PEREGRINE within PANTHER.

This schema shows what information will be made available within the PANTHER website. A. Gene detail page. Each gene in PANTHER has a gene detail page which now includes an Enhancers section (circled in red) with a link to view all enhancers associated with that gene by PEREGRINE. B. Enhancer detail page. Each enhancer has an enhancer detail page in PANTHER with the enhancer’s ID, genomic location, original source, and detailed information on the experimental evidence used by PERGERINE to link that enhancer each of its associated genes. (Screenshots of the PANTHER website⁴⁵ published under CC BY license with permission from the original copyright holder).

Fig 6. Comparison of PEREGRINE enhancers with HACER and GeneHancer enhancers.

Percentages are in terms of the enhancer set that the percentage labels are in. a. HACER and PEREGRINE enhancer overlap in terms of percentages of numbers of enhancers from each source. b. HACER and PEREGRINE enhancer clusters overlapped in terms of percentages of numbers of clusters from each source. c. GeneHancer and PEREGRINE enhancer overlap in terms of percentages of numbers of enhancers from each source. d. GeneHancer and PEREGRINE enhancer clusters overlapped in terms of percentages of numbers of clusters from each source.