Androgen receptor uses relaxed response element stringency for selective chromatin binding and transcriptional regulation <i>in vivo</i>

Sahu, Biswajyoti; Pihlajamaa, Päivi; Dubois, Vanessa; Kerkhofs, Stefanie; Claessens, Frank; Jänne, Olli A.

doi:10.1093/nar/gkt1401

Cited by 55 publications

(46 citation statements)

References 33 publications

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“…These in vivo studies thus confirmed the existence of selective AREs and their significance for genome-wide AR-binding events and transcription programs (105,107,108). Analysis of the sequences specific for the wild-type AR identified a response element with a well-conserved 5Ј hexamer but marginal sequence conservation of the 3Ј hexamer -only a G at position 11 is highly conserved -, whereas the canonical ARE/GRE (an inverted repeat of the 5Ј-AGAACA-3Ј hexamer) was enriched among the shared AR binding sites, ie, the sites that both wild-type and SPARKI AR recognized equally well (108).…”

Section: B Response Elements: Shared and Selective For Arsupporting

confidence: 57%

“…Our in vivo ChIP-seq study revealed differential genome-wide chromatin binding between wild-type and SPARKI AR, with a significant proportion of wild-type ARBs being lost in epididymides and prostates of SPARKI mice, highlighting a subgroup of in vivo AR-binding events that are highly dependent on the second zinc finger of the receptor (108). These in vivo studies thus confirmed the existence of selective AREs and their significance for genome-wide AR-binding events and transcription programs (105,107,108).…”

Section: B Response Elements: Shared and Selective For Armentioning

confidence: 84%

“…Thus, AR-selective receptor binding in vivo is achieved through relaxed cis-element stringency rather than a distinct and strict ARE sequence, most likely due to the highaffinity protein-protein interaction at the AR DBD dimer interphase (109). Of note, the previous suggestion that the cis-element of a selective ARE is a direct repeat of the 5Ј-AGAACA-3Ј sequence is not a general rule for AR selectivity (108). Owing to the relaxed sequence requirement for the second hexamer, a selective ARE can occasionally resemble also a direct repeat.…”

Section: B Response Elements: Shared and Selective For Armentioning

confidence: 97%

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Determinants of Receptor- and Tissue-Specific Actions in Androgen Signaling

2015

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The physiological androgens testosterone and 5α-dihydrotestosterone regulate the development and maintenance of primary and secondary male sexual characteristics through binding to the androgen receptor (AR), a ligand-dependent transcription factor. In addition, a number of nonreproductive tissues of both genders are subject to androgen regulation. AR is also a central target in the treatment of prostate cancer. A large number of studies over the last decade have characterized many regulatory aspects of the AR pathway, such as androgen-dependent transcription programs, AR cistromes, and coregulatory proteins, mostly in cultured cells of prostate cancer origin. Moreover, recent work has revealed the presence of pioneer/licensing factors and chromatin modifications that are important to guide receptor recruitment onto appropriate chromatin loci in cell lines and in tissues under physiological conditions. Despite these advances, current knowledge related to the mechanisms responsible for receptor- and tissue-specific actions of androgens is still relatively limited. Here, we review topics that pertain to these specificity issues at different levels, both in cultured cells and tissues in vivo, with a particular emphasis on the nature of the steroid, the response element sequence, the AR cistromes, pioneer/licensing factors, and coregulatory proteins. We conclude that liganded AR and its DNA-response elements are required but are not sufficient for establishment of tissue-specific transcription programs in vivo, and that AR-selective actions over other steroid receptors rely on relaxed rather than increased stringency of cis-elements on chromatin.

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Section: B Response Elements: Shared and Selective For Arsupporting

confidence: 57%

Section: B Response Elements: Shared and Selective For Armentioning

confidence: 84%

Section: B Response Elements: Shared and Selective For Armentioning

confidence: 97%

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Determinants of Receptor- and Tissue-Specific Actions in Androgen Signaling

2015

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“…2 a Logo presentation of top-enriched ARE motifs provided by Cheung based on [99] ( top ) and top-enriched GRE motifs from [35] ( bottom ). b Logo presentation of top-enriched ARE motifs specific for the SPARKI model, considered to be selAREs ( top ) or for classical AREs ( bottom ).Adapted from [48] …”

Section: Comparing the Dna-binding Domains Of Ar And Grmentioning

confidence: 99%

Comparing the rules of engagement of androgen and glucocorticoid receptors

Claessens

Joniau

Helsen

2017

Cell. Mol. Life Sci.

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Despite the diverse physiological activities of androgens and glucocorticoids, the corresponding receptors are very close members of the nuclear-receptor super family. Their action mechanisms show striking similarities, since both receptors recognize very similar DNA-response elements and recruit the same coactivators to their target genes. The specificity of the responses lies mainly in the tissue-specific expression of the receptors and in their ligand specificity. In cells, where both receptors are expressed, the mechanisms leading to the difference in target genes are less obvious. They lie in part in subtle variations of the DNA-binding sites, in cooperativity with other transcription factors and in differential allosteric signals from the DNA and ligand to other receptor domains. We will highlight the different suggestions that might explain the DNA sequence selectivity and will compare the possible allosteric routes between the response elements and the different functions in the transactivation process. The interplay of androgen and glucocorticoid receptors is also highly relevant in clinical settings, where both receptors are therapeutically targeted. We will discuss the possibility that the glucocorticoid and androgen receptors can play partially redundant roles in castration-resistant prostate cancer.

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“…It is now clear that the selective modes of AR-ARE interaction are not due to different dimerization patterns of AR at AREs (head-to-head versus head-to-tail (Shaffer, et al 2004)) as originally thought. Rather, recent ChIP-Seq data have clarified that AR binds to selective AREs because of less stringent sequence requirements for the 3′ hexamer (Sahu, et al 2014). Recent bioinformatics-guided modeling of the ARE motifs derived from similar high-throughput studies indicated that only a minority of the AREs fit perfectly the consensus AGAACAnnnTGTTCT 15-mer motif (Wilson, et al 2016).…”

Section: Diversity In Ar-dna Interactionsmentioning

confidence: 99%

Rationale for the development of alternative forms of androgen deprivation therapy

Kumari¹,

Senapati²,

Heemers³

2017

Endocrine-Related Cancer

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With few exceptions, the almost 30,000 prostate cancer deaths annually in the United States are due to failure of androgen deprivation therapy. Androgen deprivation therapy prevents ligand-activation of the androgen receptor. Despite initial remission after androgen deprivation therapy, prostate cancer almost invariably progresses while continuing to rely on androgen receptor action. Androgen receptor's transcriptional output, which ultimately controls prostate cancer behavior, is an alternative therapeutic target, but its molecular regulation is poorly understood. Recent insights in the molecular mechanisms by which the androgen receptor controls transcription of its target genes are uncovering gene specificity as well as context-dependency. Heterogeneity in the androgen receptor's transcriptional output is reflected both in its recruitment to diverse cognate DNA binding motifs and in its preferential interaction with associated pioneering factors, other secondary transcription factors and coregulators at those sites. This variability suggests that multiple, distinct modes of androgen receptor action that regulate diverse aspects of prostate cancer biology and contribute differentially to prostate cancer's clinical progression are active simultaneously in prostate cancer cells. Recent progress in the development of peptidomimetics and small molecules, and application of Chem-Seq approaches indicate the feasibility for selective disruption of critical protein-protein and protein-DNA interactions in transcriptional complexes. Here, we review the recent literature on the different molecular mechanisms by which the androgen receptor transcriptionally controls prostate cancer progression, and we explore the potential to translate these insights into novel, more selective forms of therapies that may bypass prostate cancer's resistance to conventional androgen deprivation therapy.

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Androgen receptor uses relaxed response element stringency for selective chromatin binding and transcriptional regulation in vivo

Cited by 55 publications

References 33 publications

Determinants of Receptor- and Tissue-Specific Actions in Androgen Signaling

Determinants of Receptor- and Tissue-Specific Actions in Androgen Signaling

Comparing the rules of engagement of androgen and glucocorticoid receptors

Rationale for the development of alternative forms of androgen deprivation therapy

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