Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer.
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Date
2017-03-31ICR Author
Author
Zuber, V
Bettella, F
Witoelar, A
PRACTICAL Consortium,
CRUK GWAS,
BCAC Consortium,
TRICL Consortium,
Andreassen, OA
Mills, IG
Urbanucci, A
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. RESULTS: Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. CONCLUSIONS: This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.
Collections
Subject
PRACTICAL Consortium
CRUK GWAS
BCAC Consortium
TRICL Consortium
Humans
Breast Neoplasms
Prostatic Neoplasms
Genetic Predisposition to Disease
Cell Cycle Proteins
Nuclear Proteins
Histones
Receptors, Androgen
Transcription Factors
Chromosome Mapping
Computational Biology
Organ Specificity
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Binding Sites
Protein Binding
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Female
Male
Enhancer Elements, Genetic
Genome-Wide Association Study
Research team
Oncogenetics
Language
eng
Date accepted
2017-03-11
License start date
2017-03-31
Citation
BMC genomics, 2017, 18 (1), pp. 270 - ?
Publisher
BIOMED CENTRAL LTD
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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