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

Zhifei Luo, Suhn Kyong Rhie, Fides D. Lay, Peggy J. Farnham

Research output: Contribution to journalArticle

21 Scopus citations

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. Luo et al. identify an 800-kb loop between a prostate cancer risk region and HOXA13. Deleting the risk region removes one anchor point of the repressive loop and upregulates HOXA13, leading to changes in the transcriptome, including overexpression of an oncogene (GATA2).

Original languageEnglish (US)
Pages (from-to)1411-1417
Number of pages7
JournalCell Reports
Volume21
Issue number6
DOIs
StatePublished - Nov 7 2017
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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