Cell type-selective disease-association of genes under high regulatory load.
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.
Life Sciences Research Unit, University of Luxembourg, L-1511 Luxembourg, Luxembourg.
Mafalda
M
Galhardo
Biozentrum, University of Basel and Swiss Institute of Bioinformatics, 4056 Basel, Switzerland.
Philipp
P
Berninger
Life Sciences Research Unit, University of Luxembourg, L-1511 Luxembourg, Luxembourg.
Thanh-Phuong
TP
Nguyen
Life Sciences Research Unit, University of Luxembourg, L-1511 Luxembourg, Luxembourg.
Thomas
T
Sauter
Life Sciences Research Unit, University of Luxembourg, L-1511 Luxembourg, Luxembourg lasse.sinkkonen@uni.lu.
Lasse
L
Sinkkonen
D020413:3' Untranslated Regions; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004194:Disease / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; D035683:MicroRNAs; D014157:Transcription Factors