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high regulatory load; epigenomics; active enhancer; disease-association; microRNA; transcription factor
Abstract :
[en] We previously showed that disease-linked metabolic genes are often under combinatorial regulation. Using the genome-wide ChIP-Seq binding profiles for 93 transcription factors in nine different cell lines, we show that genes under high regulatory load are significantly enriched for disease-association across cell types. We find that transcription factor load correlates with the enhancer load of the genes and thereby allows the identification of genes under high regulatory load by epigenomic mapping of active enhancers. Identification of the high enhancer load genes across 139 samples from 96 different cell and tissue types reveals a consistent enrichment for disease-associated genes in a cell type-selective manner. The underlying genes are not limited to super-enhancer genes and show several types of disease-association evidence beyond genetic variation (such as biomarkers). Interestingly, the high regulatory load genes are involved in more KEGG pathways than expected by chance, exhibit increased betweenness centrality in the interaction network of liver disease genes, and carry longer 3'UTRs with more microRNA (miRNA) binding sites than genes on average, suggesting a role as hubs integrating signals within regulatory networks. In summary, epigenetic mapping of active enhancers presents a promising and unbiased approach for identification of novel disease genes in a cell type-selective manner.
Research center :
ULHPC - University of Luxembourg: High Performance Computing
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Galhardo, Mafalda Sofia ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Berninger, Philipp; University of Basel > Biozentrum
Nguyen, Thanh-Phuong ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Sauter, Thomas ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Sinkkonen, Lasse ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
External co-authors :
yes
Language :
English
Title :
Cell type-selective disease-association of genes under high regulatory load