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Cell Rep. 2017 Nov 7;21(6):1411-1417. doi: 10.1016/j.celrep.2017.10.048.

A Prostate Cancer Risk Element Functions as a Repressive Loop that Regulates HOXA13.

Author information

1
Department of Biochemistry and Molecular Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
2
Department of Biochemistry and Molecular Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: peggy.farnham@med.usc.edu.

Abstract

Prostate cancer (PCa) is the leading cancer among men in the United States, with genetic factors contributing to ∼42% of the susceptibility to PCa. We analyzed a PCa risk region located at 7p15.2 to gain insight into the mechanisms by which this noncoding region may affect gene regulation and contribute to PCa risk. We performed Hi-C analysis and demonstrated that this region has long-range interactions with the HOXA locus, located ∼873 kb away. Using the CRISPR/Cas9 system, we deleted a 4-kb region encompassing several PCa risk-associated SNPs and performed RNA-seq to investigate transcriptomic changes in prostate cells lacking the regulatory element. Our results suggest that the risk element affects the expression of HOXA13 and HOTTIP, but not other genes in the HOXA locus, via a repressive loop. Forced expression of HOXA13 was performed to gain further insight into the mechanisms by which this risk element affects PCa risk.

KEYWORDS:

CRISPR; GWAS; HOX genes; Hi-C; chromatin structure; transcriptional regulation

PMID:
29117547
PMCID:
PMC5726543
DOI:
10.1016/j.celrep.2017.10.048
[Indexed for MEDLINE]
Free PMC Article

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