Abstract

Background

Revealing the gene targets of distal regulatory elements is challenging yet critical for interpreting regulome data. Experiment-derived enhancer-gene links are restricted to a small set of enhancers and/or cell types, while the accuracy of genome-wide approaches remains elusive due to the lack of a systematic evaluation. We combined multiple spatial and in silico approaches for defining enhancer locations and linking them to their target genes aggregated across >500 cell types, generating 1860 human genome-wide distal enhancer-to-target gene definitions (EnTDefs). To evaluate performance, we used gene set enrichment (GSE) testing on 87 independent ENCODE ChIP-seq datasets of 34 transcription factors (TFs) and assessed concordance of results with known TF Gene Ontology annotations, and other benchmarks.

Results

The top ranked 741 (40%) EnTDefs significantly outperform the common, naïve approach of linking distal regions to the nearest genes, and the top 10 EnTDefs perform well when applied to ChIP-seq data of other cell types. The GSE-based ranking of EnTDefs is highly concordant with ranking based on overlap with curated benchmarks of enhancer-gene interactions. Both our top general EnTDef and cell-type-specific EnTDefs significantly outperform seven independent computational and experiment-based enhancer-gene pair datasets. We show that using our top EnTDefs for GSE with either genome-wide DNA methylation or ATAC-seq data is able to better recapitulate the biological processes changed in gene expression data performed in parallel for the same experiment than our lower-ranked EnTDefs.

Conclusions

Our findings illustrate the power of our approach to provide genome-wide interpretation regardless of cell type.

Details

Title
Comprehensive enhancer-target gene assignments improve gene set level interpretation of genome-wide regulatory data
Author
Qin, Tingting; Lee, Christopher; Li, Shiting; Cavalcante, Raymond G; Orchard, Peter; Yao, Heming; Zhang, Hanrui; Wang, Shuze; Patil, Snehal; Boyle, Alan P; Sartor, Maureen A  VIAFID ORCID Logo 
Pages
1-30
Section
Research
Publication year
2022
Publication date
2022
Publisher
BioMed Central
ISSN
14747596
e-ISSN
1474760X
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2666609208
Copyright
© 2022. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.