Event Details

Friday, 08 June 2018
12:30 pm - 1:30 pm
QBP Auditorium
UQ Location:
Queensland Bioscience Precinct (St Lucia)
Event category(s):

Event Contact

Ms Katrina Garner-Moore
3346 2133
Org. Unit:
Institute for Molecular Bioscience

Event Description

Full Description:
Decoding the noncoding: deciphering how genetic variants modify breast cancer risk.

Associate Professor Juliet French is Head of the Functional Genetics Laboratory at QIMR Berghofer. She conducted her PhD and post-doctoral studies at UQ with a research focus on mechanisms of gene regulation. Her research is aimed at understanding how genetic variants in non-coding regions of the genome influence cancer risk and progression. A major interest of her laboratory is the functional follow-up of breast cancer risk loci identified by Genome Wide Association Studies (GWAS). GWAS have identified 196 loci associated with breast cancer. Fine-mapping of these regions has shown that the putative causative variants at each locus fall outside protein-coding regions. Recent analysis has shown that many breast cancer risk variants fall in regulatory elements such as transcriptional enhancers, however the contribution of long non-coding RNAs (lncRNA) is still currently unknown.

Using targeted RNA sequencing combined with de novo transcript assembly we systematically annotated multi-exonic lncRNAs transcribed from 1.5Mb intervals surrounding breast cancer GWAS loci and assessed their contribution to breast cancer risk. We identified >3000 lncRNA genes and show that breast cancer risk variants are significantly enriched in lncRNA exons but not the promoters or introns. Using eQTL and allele expression imbalance analyses we identified several lncRNAs whose expression are associated with risk variants. Approximately half of these variants fell within lncRNA exons suggesting that the variants may alter the stability of transcripts, the remainder were located more distally. Using Capture Hi-C data, we provide evidence that these risk variants fall in distal enhancers that regulate lncRNA genes through long-range chromatin interactions.

One example of this mechanism is the 11q13 risk locus. At this locus, we show that breast cancer risk variants fall in an enhancer of two novel estrogen-regulated lncRNAs, we named CUPID1 and CUPID2. We provide evidence that the risk variants are associated with allelic imbalance of CUPID1 and reduced chromatin looping between the enhancer and the CUPID1/2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone receptor-positive breast tumors and play a role in modulating double strand break (DSB) repair pathway choice. These data reveal a novel mechanism for the involvement of this region in breast cancer.

Directions to UQ

Google Map:
To St Lucia Campus, UQ Ipswich, and UQ Gatton.

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