4.8 Article

A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer

Journal

NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-17325-y

Keywords

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Funding

  1. Department of Atomic Energy, Government of India [12-RD-TFR-5.04-0800]
  2. NCBS-TIFR
  3. Welcome-IA [IA/1/14/2/501539]
  4. SERB [CRG/2019/005714]
  5. Ramanujan Fellowship (SERB) [SB/S2/RJN-071/2018]
  6. DOD [PC180367]
  7. NIH [R01CA193910, R01CA227237]
  8. Shyama Prasad Mukherjee fellowship from CSIR, India
  9. Dept. of Biotechnology (Govt. of India) junior research fellowship
  10. NCBS/TIFR graduate program
  11. [R01 CA165862]
  12. [U19CA214253]

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Genetic variation at the 8q24 locus is linked with the greater susceptibility to prostate cancer in men of African ancestry. One such African ancestry specific rare variant, rs72725854 (A>G/T) (similar to 6% allele frequency) has been associated with a similar to 2-fold increase in prostate cancer risk. However, the functional relevance of this variant is unknown. Here we show that the variant rs72725854 is present in a prostate cancer-specific enhancer at 8q24 locus. Chromatin-conformation capture and dCas9 mediated enhancer blocking establish a direct regulatory link between this enhancer and lncRNAs PCAT1, PRNCR1 and PVT1. The risk allele ('T') is associated with higher expression of PCAT1, PVT1 and c-myc in prostate tumors. Further, enhancer with the risk allele gains response to androgen stimulation by recruiting the transcription factor SPDEF whereas, non-risk alleles remain non-responsive. Elevated expression of these lncRNAs and c-myc in risk allele carriers may explain their greater susceptibility to prostate cancer.

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