Comprehensive enhancer-target gene assignments improve gene set level interpretation of genome-wide regulatory data.
Genome Biol
; 23(1): 105, 2022 04 26.
Article
en En
| MEDLINE
| ID: mdl-35473573
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Secuencias Reguladoras de Ácidos Nucleicos
/
Secuenciación de Inmunoprecipitación de Cromatina
Límite:
Humans
Idioma:
En
Revista:
Genome Biol
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos