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Nucleic Acids Res. 2015 Oct 15;43(18):8839-55. doi: 10.1093/nar/gkv863. Epub 2015 Sep 3.

Cell type-selective disease-association of genes under high regulatory load.

Author information

1
Life Sciences Research Unit, University of Luxembourg, L-1511 Luxembourg, Luxembourg.
2
Biozentrum, University of Basel and Swiss Institute of Bioinformatics, 4056 Basel, Switzerland.
3
Life Sciences Research Unit, University of Luxembourg, L-1511 Luxembourg, Luxembourg lasse.sinkkonen@uni.lu.

Abstract

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.

PMID:
26338775
PMCID:
PMC4605313
DOI:
10.1093/nar/gkv863
[Indexed for MEDLINE]
Free PMC Article

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