Abstract
BackgroundEfforts to elucidate the function of enhancers in vivo are underway but their vast numbers alongside differing enhancer architectures make it difficult to determine their impact on gene activity. By systematically annotating multiple mouse tissues with super- and typical-enhancers, we have explored their relationship with gene function and phenotype.ResultsThough super-enhancers drive high total- and tissue-specific expression of their associated genes, we find that typical-enhancers also contribute heavily to the tissue-specific expression landscape on account of their large numbers in the genome. Unexpectedly, we demonstrate that both enhancer types are preferentially associated with relevant ‘tissue-type’ phenotypes and exhibit no difference in phenotype effect size or pleiotropy. Modelling regulatory data alongside molecular data, we built a predictive model to infer gene-phenotype associations and use this model to predict potentially novel disease-associated genes.ConclusionOverall our findings reveal that differing enhancer architectures have a similar impact on mammalian phenotypes whilst harbouring differing cellular and expression effects. Together, our results systematically characterise enhancers with predicted phenotypic traits endorsing the role for both types of enhancers in human disease and disorders.
Highlights
Efforts to elucidate the function of enhancers in vivo are underway but their vast numbers alongside differing enhancer architectures make it difficult to determine their impact on gene activity
Distribution of constituent enhancers associated with TEs, referred to as typical-enhancer class (TEC); and (3) gene-tissue pairs associated with weak/ poised enhancers, referred to as weak-enhancer class (WEC). We found that both super-enhancer class (SEC) and TEC are associated with highly expressed genes in comparison to the WEC (SEC: effect size (ES) = 0.95, p < 2.2 × 10− 16; TEC: ES = 0.86, p < 2.2 × 10− 16; Wilcoxon Rank Sum Test) but that the SEC appears to have the highest level of total-expression (SEC compared to TEC: ES = 0.56, p < 2.2 × 10− 16) (Fig. 2a, Additional file 1: Figure S7a)
We investigated the mammalian phenotype and disease associations of SE and TE associated genes. We identified that both the SEC and TEC are significantly enriched in phenotypes and diseases in the corresponding tissue-types (Fig. 3), emphasising that phenotypes are governed by tissue-specific enhancers
Summary
Efforts to elucidate the function of enhancers in vivo are underway but their vast numbers alongside differing enhancer architectures make it difficult to determine their impact on gene activity. Most important factors among these include the Mediator complex, which is a co-activator complex binding to other TFs and RNA polymerase II [15]; cohesin, which stabilises and sometimes even drives cell-type specific enhancer-promoter communication bridges [15]; and factors important for paused RNA polymerase II release and elongation such as BRD4 [16] How these interactions and chromatin looping are established remains largely unknown. Phenotyping initiatives like the International Mouse Phenotyping Consortium (IMPC) [22, 23] identify phenotype-genotype associations by producing mouse lines with a protein-coding gene knockout and systematically recording the results from a battery of phenotyping tests for each line These standardised tests cover a multitude of biological processes and provide consistent descriptions of phenotypes for each functional gene, which can be used in the understanding of human traits and diseases. Despite recent progress in the study of the non-coding genome, systematic genotype-phenotype analysis of enhancers and other non-coding regions remains a substantial challenge
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