A holistic view of mouse enhancer architectures reveals analogous pleiotropic effects and correlation with human disease

BMC Genomics

Steve D. M. Brown¹  Ann-Marie Mallon¹  Siddharth Sethi¹  Simon Greenaway¹  Michelle M. Simon¹  John Williams²  Ilya E. Vorontsov³  Ivan V. Kulakovskiy⁴  Vsevolod J. Makeev⁵ 

[1] Mammalian Genetics Unit, MRC Harwell Institute, OX11 0RD, Oxfordshire, UK;Mammalian Genetics Unit, MRC Harwell Institute, OX11 0RD, Oxfordshire, UK;Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, B15 2TH, Birmingham, UK;Institute of Cancer and Genomic Sciences, University of Birmingham, B15 2TT, Birmingham, UK;Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkina 3, 119991, Moscow, Russia;Institute of Protein Research, Russian Academy of Sciences, Institutskaya 4, 142290, Pushchino, Moscow Region, Russia;Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkina 3, 119991, Moscow, Russia;Institute of Protein Research, Russian Academy of Sciences, Institutskaya 4, 142290, Pushchino, Moscow Region, Russia;Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, 119991, Moscow, Russia;Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkina 3, 119991, Moscow, Russia;Institute of Protein Research, Russian Academy of Sciences, Institutskaya 4, 142290, Pushchino, Moscow Region, Russia;Moscow Institute of Physics and Technology, 9 Institutskiy per., 141700, Dolgoprudny, Moscow Region, Russia;

关键词: Super-enhancers;    Typical-enhancers;    Tissue-specificity;    Expression;    Phenotypes;    Protein-protein interactions;    Transcription factors;    Gene-phenotype prediction;   

DOI  :  10.1186/s12864-020-07109-5

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY