Oncotarget

Research Papers:

In-silico identification and functional validation of allele-dependent AR enhancers

Sonia Garritano _, Alessandro Romanel, Yari Ciribilli, Alessandra Bisio, Antoneta Gavoci, Alberto Inga and Francesca Demichelis

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Oncotarget. 2015; 6:4816-4828. https://doi.org/10.18632/oncotarget.3019

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Abstract

Sonia Garritano1,*, Alessandro Romanel1,*, Yari Ciribilli2,*, Alessandra Bisio2, Antoneta Gavoci1, Alberto Inga2,#, Francesca Demichelis1,3,4,#

1Laboratory of Computational Oncology, CIBIO, Centre for Integrative Biology, University of Trento, Italy

2Laboratory of Transcriptional Networks, CIBIO, Centre for Integrative Biology, University of Trento, Italy

3HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY, USA

4Institute for Precision Medicine, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY, USA

*These authors have contributed equally to this work

#These authors share senior authorship

Correspondence to:

Francesca Demichelis, e-mail: demichelis@science.unitn.it

Keywords: Androgen Receptor (AR), polymorphic regulatory regions, enhancer, allele-specific, Estrogen Receptor (ER)

Received: November 19, 2014     Accepted: December 30, 2014     Published: February 27, 2015

ABSTRACT

Androgen Receptor (AR) and Estrogen Receptors (ERs) are key nuclear receptors that can cooperate in orchestrating gene expression programs in multiple tissues and diseases, targeting binding elements in promoters and distant enhancers. We report the unbiased identification of enhancer elements bound by AR and ER-α whose activity can be allele-specific depending on the status of nearby Single Nucleotide Polymorphisms (SNP). ENCODE data were computationally mined to nominate genomic loci with: (i) chromatin signature of enhancer activity from activation histone marks, (ii) binding evidence by AR and ER-α, (iii) presence of a SNP. Forty-one loci were identified and two, on 1q21.3 and 13q34, selected for characterization by gene reporter, Chromatin immunoprecipitation (ChIP) and RT-qPCR assays in breast (MCF7) and prostate (PC-3) cancer-derived cell lines. We observed allele-specific enhancer activity, responsiveness to ligand-bound AR, and potentially influence on the transcription of closely located genes (RAB20, ING1, ARHGEF7, ADAM15). The 1q21.3 variant, rs2242193, showed impact on AR binding in MCF7 cells that are heterozygous for the SNP. Our unbiased genome-wide search proved to be an efficient methodology to discover new functional polymorphic regulatory regions (PRR) potentially acting as risk modifiers in hormone-driven cancers and overall nominated SNPs in PRR across 136 transcription factors.


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