An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells

Abstract

The aberrant activities of transcription factors such as the androgen receptor (AR) underpin prostate cancer development. While the AR cis-regulation has been extensively studied in prostate cancer, information pertaining to the spatial architecture of the AR transcriptional circuitry remains limited. In this paper, we propose a novel framework to profile long-range chromatin interactions associated with AR and its collaborative transcription factor, erythroblast transformation-specific related gene (ERG), using chromatin interaction analysis by paired-end tag (ChIA-PET). We identified ERG-associated long-range chromatin interactions as a cooperative component in the AR-associated chromatin interactome, acting in concert to achieve coordinated regulation of a subset of AR target genes. Through multifaceted functional data analysis, we found that AR-ERG interaction hub regions are characterized by distinct functional signatures, including bidirectional transcription and cotranscription factor binding. In addition, cancer-associated long noncoding RNAs were found to be connected near protein-coding genes through AR-ERG looping. Finally, we found strong enrichment of prostate cancer genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) at AR-ERG co-binding sites participating in chromatin interactions and gene regulation, suggesting GWAS target genes identified from chromatin looping data provide more biologically relevant findings than using the nearest gene approach. Taken together, our results revealed an AR-ERG-centric higher-order chromatin structure that drives coordinated gene expression in prostate cancer progression and the identification of potential target genes for therapeutic intervention.

Modulation of androgen receptor DNA binding activity through direct interaction with the ETS transcription factor ERG

“…Specifically, we found that ERG stimulates AR binding to high affinity palindromic ARE DNA consensus sites, as well as lower affinity ARE half sites, independent of an ETS consensus motif. The optimal 6-to 7-base pair spacing between AR and ETS binding sites that we observed on AR-ERG codependent genes in cells and in our synthetic dsDNA templates is intriguing and invokes at least two possible models: 1) that DNA can assist in orienting the two proteins for subsequent protein-protein interaction, and 2) that ERG can stimulate AR's binding to DNA independent of ERG's own DNA binding, consistent with recent evidence suggesting that AR and ERG form long-range interactions through chromosomal looping (55). Our biochemical observations also provide insight to previous findings in cancer cells that ERG amplification expands the AR cistrome to genes that otherwise have low AR occupancy (18)(19)(20), and that ETS factors can modulate AR binding to DNA when AR is otherwise impaired (Figs.…”

Association of germline genetic variants with TMPRSS2-ERG fusion status in prostate cancer

“…Similar associations have been observed for GWAS identified genomic loci with the risk of ERnegative disease in breast cancer subtypes [54]. Further, functional analysis based on long range chromatin interactomes analysis in CaP cells has shown strong enrichment of CaP GWAS SNPs at AR-ERG co-binding sites participating in chromatin interactions and gene regulation, suggesting potential functional role of these SNPs towards specific ERG subtype [55].…”

Androgen receptor enhancer usage and the chromatin regulatory landscape in human prostate cancers

“…It would be therefore of interest to perform for example promoter capture Hi-C, both in hormone-deprived as well as hormone-stimulated prostate cancer cell lines to characterize the AR enhancer-target gene interactome along with the potential dynamics thereof. Very recently, AR-centered chromatin interactions in VCaP cells were mapped with ChIA-PET (Zhang et al 2019).…”