IMPACT: Genomic Annotation of Cell-State-Specific Regulatory Elements Inferred from the Epigenome of Bound Transcription Factors.
Am J Hum Genet
; 104(5): 879-895, 2019 05 02.
Article
em En
| MEDLINE
| ID: mdl-31006511
ABSTRACT
Despite significant progress in annotating the genome with experimental methods, much of the regulatory noncoding genome remains poorly defined. Here we assert that regulatory elements may be characterized by leveraging local epigenomic signatures where specific transcription factors (TFs) are bound. To link these two features, we introduce IMPACT, a genome annotation strategy that identifies regulatory elements defined by cell-state-specific TF binding profiles, learned from 515 chromatin and sequence annotations. We validate IMPACT using multiple compelling applications. First, IMPACT distinguishes between bound and unbound TF motif sites with high accuracy (average AUPRC 0.81, SE 0.07; across 8 tested TFs) and outperforms state-of-the-art TF binding prediction methods, MocapG, MocapS, and Virtual ChIP-seq. Second, in eight tested cell types, RNA polymerase II IMPACT annotations capture more cis-eQTL variation than sequence-based annotations, such as promoters and TSS windows (25% average increase in enrichment). Third, integration with rheumatoid arthritis (RA) summary statistics from European (N = 38,242) and East Asian (N = 22,515) populations revealed that the top 5% of CD4+ Treg IMPACT regulatory elements capture 85.7% of RA h2, the most comprehensive explanation for RA h2 to date. In comparison, the average RA h2 captured by compared CD4+ T histone marks is 42.3% and by CD4+ T specifically expressed gene sets is 36.4%. Lastly, we find that IMPACT may be used in many different cell types to identify complex trait associated regulatory elements.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artrite Reumatoide
/
Fatores de Transcrição
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Genoma Humano
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Sequências Reguladoras de Ácido Nucleico
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Anotação de Sequência Molecular
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Epigenômica
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Epigenoma
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Am J Hum Genet
Ano de publicação:
2019
Tipo de documento:
Article