Androgen receptor enhancer usage and the chromatin regulatory landscape in human prostate cancers
in Endocrine-Related Cancer
Authors: Suzan Stelloo 1 , Andries M Bergman 2 , 3 and Wilbert Zwart 1 , 4
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0 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands 1 Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands 2 Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 3 Department of Biomedical Engineering, Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
Correspondence should be addressed to W Zwart: w.zwart@nki.nl
DOI: https://doi.org/10.1530/ERC-19-0032
Page(s): R267–R285
Volume/Issue: Volume 26: Issue 5
Article Type: Review Article
Online Publication Date: May 2019
Copyright: © 2019 Society for Endocrinology 2019
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Abstract
The androgen receptor (AR) is commonly known as a key transcription factor in prostate cancer development, progression and therapy resistance. Genome-wide chromatin association studies revealed that transcriptional regulation by AR mainly depends on binding to distal regulatory enhancer elements that control gene expression through chromatin looping to gene promoters. Changes in the chromatin epigenetic landscape and DNA sequence can locally alter AR-DNA-binding capacity and consequently impact transcriptional output and disease outcome. The vast majority of reports describing AR chromatin interactions have been limited to cell lines, identifying numerous other factors and interacting transcription factors that impact AR chromatin interactions. Do these factors also impact AR cistromics – the genome-wide chromatin-binding landscape of AR – in vivo? Recent technological advances now enable researchers to identify AR chromatin-binding sites and their target genes in human specimens. In this review, we provide an overview of the different factors that influence AR chromatin binding in prostate cancer specimens, which is complemented with knowledge from cell line studies. Finally, we discuss novel perspectives on studying AR cistromics in clinical samples.
Transcription factor binding
By 2003, the DNA sequence of the entire human genome was annotated by The Human Genome Project (International Human Genome Sequencing Consortium 2004). However, as informative the primary DNA sequence information is on the protein-coding genome (~2% of the total human DNA), interpretation of the remaining ~98% of the human genome appears more challenging. One of the major challenges in functionally interpreting the non-protein-coding human genome is that the primary sequence itself does not explain how the DNA is packaged into chromatin and where transcription factors (TFs) bind. Some TFs bind indirectly to the DNA via protein–protein interactions by means of tethering, while other TFs recognize specific DNA sequences, often referred to as TF motifs, footprints or grammar (Fig. 1A). Many computational methods have been developed to scan for these TF motifs across the entire genome to predict the capacity of a particular TF to bind specific regions, such as the SeqPos motif tool (Liu et al. 2011) and HOMER (Heinz et al. 2010). In addition, other algorithms (e.g. MEME Suite; Bailey et al. 2015) can be applied to discover DNA sequence patterns in given regions. However, the presence of a TF motif does not imply that the TF is actually capable to bind this region. For example, the AR – the main driver in prostate cancer development and progression – recognizes a palindromic dihexameric androgen-responsive element (ARE), 5′-AGAACAnnnTGTTCT-3′ (Fig. 1B), which occurs a few million times throughout the human genome. However, only hundreds to tens of thousands AREs appear to be functionally active in a given context and occupied by AR in prostate cell lines (Yu et al. 2010, Massie et al. 2011, Toropainen et al. 2016, McNair et al. 2017, Stelloo et al. 2018a) and tissue samples (Sharma et al. 2013, Chen et al. 2015, Pomerantz et al. 2015, Stelloo et al. 2015, 2018b). In addition, all cells in the human body carry an identical genome; yet, TFs regulate gene expression patterns to dictate organ development and identity. Key questions to further understand AR action on a genome-wide scale are the following: Where does AR bind the genome in different contexts, and what are the biological consequences thereof? While full discussion on the biological significance of AR in prostate cancer is beyond the scope of this review, this subject has been covered elsewhere (Culig & Santer 2014, Copeland et al. 2018, Isaacs 2018, Ken-ichi 2018). Another question is how AR chromatin binding is regulated and to what degree is this context dependent? Furthermore, with more reports describing AR cistromics in clinical samples (Table 1), what did we learn from this, and how could we use this information in the clinical setting? In particular, we focus on the technological developments (Table 2) that have made the transition from cell line models toward the study of clinical specimens. This review will address these points systematically and will highlight the potential future research directions aimed to enhance our understanding of genome regulation in prostate cancer.
Figure 1
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Figure 1
Transcription factor binding and transcription. (A) Transcription factors (TFs) interact with DNA to regulate gene expression. TFs can bind the DNA directly via recognition of sequence-specific elements or indirectly through other TFs. (B) Sequence logo depicting the androgen response element (ARE, MC00468). The logo is a graphical representation of a position weight matrix (PWM), which describes the nucleotide preference at each nucleotide position within the motif. (C) Graphical representation of AR-bound enhancer–promoter interaction. Accessible chromatin regions are flanked by active histone marks, such as H3K27ac at enhancers and H3K4me3 at promoters. Ligand-bound AR dimers bind to androgen-response elements (AREs) mostly at distal intergenic or intronic regions – enhancers. These enhancers are often distally located from genes with varying distances of ~20–300 kb. Some enhancers are bi-directionally transcribed to produce eRNAs.
Citation: Endocrine-Related Cancer 26, 5; 10.1530/ERC-19-0032
in Endocrine-Related Cancer
Authors: Suzan Stelloo 1 , Andries M Bergman 2 , 3 and Wilbert Zwart 1 , 4
View Less
0 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands 1 Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands 2 Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 3 Department of Biomedical Engineering, Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
Correspondence should be addressed to W Zwart: w.zwart@nki.nl
DOI: https://doi.org/10.1530/ERC-19-0032
Page(s): R267–R285
Volume/Issue: Volume 26: Issue 5
Article Type: Review Article
Online Publication Date: May 2019
Copyright: © 2019 Society for Endocrinology 2019
Free access
Download PDF
Check for updates
Citation Alert Citation Alerts
Get Permissions
Abstract/Excerpt
Full Text
Abstract
The androgen receptor (AR) is commonly known as a key transcription factor in prostate cancer development, progression and therapy resistance. Genome-wide chromatin association studies revealed that transcriptional regulation by AR mainly depends on binding to distal regulatory enhancer elements that control gene expression through chromatin looping to gene promoters. Changes in the chromatin epigenetic landscape and DNA sequence can locally alter AR-DNA-binding capacity and consequently impact transcriptional output and disease outcome. The vast majority of reports describing AR chromatin interactions have been limited to cell lines, identifying numerous other factors and interacting transcription factors that impact AR chromatin interactions. Do these factors also impact AR cistromics – the genome-wide chromatin-binding landscape of AR – in vivo? Recent technological advances now enable researchers to identify AR chromatin-binding sites and their target genes in human specimens. In this review, we provide an overview of the different factors that influence AR chromatin binding in prostate cancer specimens, which is complemented with knowledge from cell line studies. Finally, we discuss novel perspectives on studying AR cistromics in clinical samples.
Transcription factor binding
By 2003, the DNA sequence of the entire human genome was annotated by The Human Genome Project (International Human Genome Sequencing Consortium 2004). However, as informative the primary DNA sequence information is on the protein-coding genome (~2% of the total human DNA), interpretation of the remaining ~98% of the human genome appears more challenging. One of the major challenges in functionally interpreting the non-protein-coding human genome is that the primary sequence itself does not explain how the DNA is packaged into chromatin and where transcription factors (TFs) bind. Some TFs bind indirectly to the DNA via protein–protein interactions by means of tethering, while other TFs recognize specific DNA sequences, often referred to as TF motifs, footprints or grammar (Fig. 1A). Many computational methods have been developed to scan for these TF motifs across the entire genome to predict the capacity of a particular TF to bind specific regions, such as the SeqPos motif tool (Liu et al. 2011) and HOMER (Heinz et al. 2010). In addition, other algorithms (e.g. MEME Suite; Bailey et al. 2015) can be applied to discover DNA sequence patterns in given regions. However, the presence of a TF motif does not imply that the TF is actually capable to bind this region. For example, the AR – the main driver in prostate cancer development and progression – recognizes a palindromic dihexameric androgen-responsive element (ARE), 5′-AGAACAnnnTGTTCT-3′ (Fig. 1B), which occurs a few million times throughout the human genome. However, only hundreds to tens of thousands AREs appear to be functionally active in a given context and occupied by AR in prostate cell lines (Yu et al. 2010, Massie et al. 2011, Toropainen et al. 2016, McNair et al. 2017, Stelloo et al. 2018a) and tissue samples (Sharma et al. 2013, Chen et al. 2015, Pomerantz et al. 2015, Stelloo et al. 2015, 2018b). In addition, all cells in the human body carry an identical genome; yet, TFs regulate gene expression patterns to dictate organ development and identity. Key questions to further understand AR action on a genome-wide scale are the following: Where does AR bind the genome in different contexts, and what are the biological consequences thereof? While full discussion on the biological significance of AR in prostate cancer is beyond the scope of this review, this subject has been covered elsewhere (Culig & Santer 2014, Copeland et al. 2018, Isaacs 2018, Ken-ichi 2018). Another question is how AR chromatin binding is regulated and to what degree is this context dependent? Furthermore, with more reports describing AR cistromics in clinical samples (Table 1), what did we learn from this, and how could we use this information in the clinical setting? In particular, we focus on the technological developments (Table 2) that have made the transition from cell line models toward the study of clinical specimens. This review will address these points systematically and will highlight the potential future research directions aimed to enhance our understanding of genome regulation in prostate cancer.
Figure 1
Download Figure
Download figure as PowerPoint slide
Figure 1
Transcription factor binding and transcription. (A) Transcription factors (TFs) interact with DNA to regulate gene expression. TFs can bind the DNA directly via recognition of sequence-specific elements or indirectly through other TFs. (B) Sequence logo depicting the androgen response element (ARE, MC00468). The logo is a graphical representation of a position weight matrix (PWM), which describes the nucleotide preference at each nucleotide position within the motif. (C) Graphical representation of AR-bound enhancer–promoter interaction. Accessible chromatin regions are flanked by active histone marks, such as H3K27ac at enhancers and H3K4me3 at promoters. Ligand-bound AR dimers bind to androgen-response elements (AREs) mostly at distal intergenic or intronic regions – enhancers. These enhancers are often distally located from genes with varying distances of ~20–300 kb. Some enhancers are bi-directionally transcribed to produce eRNAs.
Citation: Endocrine-Related Cancer 26, 5; 10.1530/ERC-19-0032
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