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

Nature Communications
Kaivalya WalavalkarDimple Notani

Abstract

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) (~6% allele frequency) has been associated with a ~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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Citations

Jan 29, 2021·Molecular Genetics and Genomics : MGG·Yanjun DingRuijie Zhang
Feb 6, 2021·Nature Reviews. Disease Primers·Richard J RebelloRobert G Bristow
Dec 18, 2020·Frontiers in Genetics·Marina AznaourovaLeon N Schulte
Apr 18, 2021·Cell·Olivia M de GoedeStephen B Montgomery

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Methods Mentioned

BETA
ChIP-seq
PCR
HiC
RNA-seq
electrophoretic mobility shift assay
transfections
transfection
Assay
immunoprecipitation
PCRs

Software Mentioned

4Cker
Juicebox
gprofiler
HOMER annotatePeaks
IGV browser
4C
ker
Bowtie2
UCSC browser
HOMER

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