A holistic view of mouse enhancer architectures reveals analogous pleiotropic effects and correlation with human disease
- PDF / 5,104,263 Bytes
- 22 Pages / 595.276 x 790.866 pts Page_size
- 66 Downloads / 177 Views
RESEARCH ARTICLE
Open Access
A holistic view of mouse enhancer architectures reveals analogous pleiotropic effects and correlation with human disease Siddharth Sethi1, Ilya E. Vorontsov2,3, Ivan V. Kulakovskiy2,3,4, Simon Greenaway1, John Williams1,5,6, Vsevolod J. Makeev2,3,7, Steve D. M. Brown1, Michelle M. Simon1* and Ann-Marie Mallon1*
Abstract Background: 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. By systematically annotating multiple mouse tissues with super- and typical-enhancers, we have explored their relationship with gene function and phenotype. Results: Though 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. Conclusion: Overall 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. Keywords: Super-enhancers, Typical-enhancers, Tissue-specificity, Expression, Phenotypes, Protein-protein interactions, Transcription factors, Gene-phenotype prediction
Background Mammalian gene expression and their parallel gene networks are tightly controlled by non-coding regulatory regions such as enhancers, their accompanying transcription factors (TFs), chromatin re-modellers and non-coding RNAs [1]. Large scale programs such as ENCODE [2], FANTOM5 [3] and NIH Roadmap Epigenomics project [4] have generated an initial detailed * Correspondence: [email protected]; [email protected] 1 Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire OX11 0RD, UK Full list of author information is available at the end of the article
exploration of active enhancer and promoter regions in a plethora of tissues and cell types forming a crucial data source for study of regulatory regions. Putative enhancers have been predicted in multiple organisms with > 1 million estimated in the mouse and human genomes [2, 5–8]. ChIP-Seq analysis of chromatin modification has been widely used to catalogue these potential enhancer and promoter regions, with enhancer loci being enriched in histone H3 lysine4 monomethylation (H3K4me1) and lacking histone H3 lysine4 trimethylation (H3K4me3), while active enhancer sites have the addition of histone H3
Data Loading...
