Steroid Receptors Reprogram FoxA1 Occupancy through Dynamic Chromatin Transitions

Swinstead, Erin E.; Miranda, Tina Branscombe; Paakinaho, Ville; Baek, Songjoon; Goldstein, Ido; Hawkins, Mary E.; Karpova, Tatiana S.; Ball, David A.; Mazza, Davide; Lavis, Luke D.; Grimm, Jonathan B.; Morisaki, Tatsuya; Grøntved, Lars; Presman, Diego M.; Hager, Gordon L.

doi:10.1016/j.cell.2016.02.067

Cited by 287 publications

(330 citation statements)

References 48 publications

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“…4C-E), contrary to observations at other genomic loci (28). This steroid-induced increase in FOXA1 occupancy is consistent with a recent study showing that FOXA1 binding can be altered by activation of steroid receptors, including ERa, in breast cancer cells (29). The AR did not display a strong enrichment over IgG controls under any treatment condition; maximal AR enrichment (2.6-fold) occurred at the positive control locus for ERa binding (pS2/TIFF1) when cells were stimulated with R1881.…”

Section: Low Highcontrasting

confidence: 52%

Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17

Selth

Tarulli

et al. 2016

Cancer Research

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Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERa), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDPglucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced diseasespecific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERa. In cell line models, ERa, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERa activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5a-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3 0 to the FOXA1 and ERa-binding sites. Although AR and FOXA1 bound the UGT promoters in ARpositive/ERa-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERa þ tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERa binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERa þ breast cancer, which may have subtypespecific consequences for disease progression and outcomes.

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Section: Low Highcontrasting

confidence: 52%

Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17

Selth

Tarulli

et al. 2016

Cancer Research

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“…The binding of a settler factor may be essential in the biological context, but it does not constitute the core pioneer activity that is restricted to initiation of chromatin opening. However for this specific example, it appears that the interaction between FoxA and nuclear receptor may be reciprocal as nuclear receptors can also recruit FoxA to specific subsets of enhancers (18).…”

Section: Pioneers Set the Stage: Assisted-loading And Settler Factorsmentioning

confidence: 99%

“…Pioneer factors tend to have higher residency time or chromatin mobility than other TFs (18,52) suggesting that stable chromatin-pioneer interactions may be critical for pioneer function. These stable pioneer-chromatin interactions may be explained by direct nucleosome binding, as shown for FoxA and the OSK pluripotency factors (29,53).…”

Section: Pioneer Interactions With Dna and Chromatinmentioning

confidence: 99%

Pioneer transcription factors shape the epigenetic landscape

Mayran

Drouin

2018

Journal of Biological Chemistry

197

145

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Pioneer transcription factors have the unique and important role of unmasking chromatin domains during development to allow the implementation of new cellular programs. Compared to those of other transcription factors, this activity implies that pioneer factors can recognize their target DNA sequences in socalled compacted or "closed" heterochromatin and can trigger remodeling of the adjoining chromatin landscape to provide accessibility to non-pioneer transcription factors. Recent studies identified several steps of pioneer action, namely rapid but weak initial binding to heterochromatin, stabilization of binding followed by chromatin opening and loss of CpG methylation that provides epigenetic memory. Whereas CpG demethylation is dependent on replication, chromatin opening is not. In this review, we highlight the unique properties of this transcription factor class and the challenges of understanding their mechanism of action.

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“…The opposite phenomenon-assisted "unloading"-has also been observed: When binding sites overlap with nucleosomes, the presence of the nucleosome speeds up the dissociation (decreases dwell time) of the TF (Luo et al 2014). Interestingly, a symmetric relationship in which steroid receptors can induce the loading of FoxA1 and vice versa has also been described (Swinstead et al 2016). However, even with cooperative interactions between components, the assembly of >70 protein subunits for a eukaryotic PIC seems like an impossible task.…”

mentioning

confidence: 99%

What have single-molecule studies taught us about gene expression?

Chen

Larson

2016

Genes Dev.

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The production of a single mRNA is the result of many sequential steps, from docking of transcription factors to polymerase initiation, elongation, splicing, and, finally, termination. Much of our knowledge about the fundamentals of RNA synthesis and processing come from ensemble in vitro biochemical measurements. Single-molecule approaches are very much in this same reductionist tradition but offer exquisite sensitivity in space and time along with the ability to observe heterogeneous behavior and actually manipulate macromolecules. These techniques can also be applied in vivo, allowing one to address questions in living cells that were previously restricted to reconstituted systems. In this review, we examine the unique insights that single-molecule techniques have yielded on the mechanisms of gene expression.Single-molecule experiments are now pervasive in biology. What started out as an experimental approach for characterizing ion channels in the 1970s (Neher and Sakmann 1976) has now become a fixture in hundreds of laboratories addressing fundamental questions in biochemistry, cell biology, genetics, and development. The methodology is nearly as diverse as the problems that are addressed and encompasses imaging, optical tweezers, atomic force microscopy, electrophysiology, and cryo-electron microscopy (cryo-EM), to list a few. The unifying principle behind these approaches is straightforward: the ability to observe the heterogeneous, rare, or fleeting behavior of macromolecules that is normally masked by ensemble techniques. In this review, we focus on the role that single-molecule approaches have played in advancing our understanding of the early steps in gene expression.In general, transcription by RNA polymerase (RNAP) in bacteria or RNA polymerase II (Pol II) in eukaryotes begins when transcription factors (TFs) are recruited to the promoter. This leads to the assembly of the preinitiation complex (PIC) that contains a semicompetent polymerase. The PIC is necessary for unwinding duplex DNA and setting the stage for processive elongation by the polymerase. After conformational changes in the PIC, the polymerase escapes the promoter region and enters into productive elongation. In eukaryotes, the nascent RNA undergoes further modifications such as addition of a 5 ′ cap, synthesis of a poly-A tail, and splicing before the mature mRNA is formed. These early steps of gene expression are uniquely suited to elucidation through singlemolecule methods. For example, single-molecule experimental approaches allow one to visualize the order of assembly for molecular complexes (i.e., the PIC) and observe the variety of pathways that can result in initiation of RNAP. The ability to observe kinetics in unperturbed systems can provide clues to the mechanisms of transcription. RNAPs can also be manipulated by singlemolecule optical trapping to reveal the inner workings of force generation by this enzyme. Furthermore, singlemolecule imaging has also revealed the heterogeneity of gene expression that exists among cells in ...

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Steroid Receptors Reprogram FoxA1 Occupancy through Dynamic Chromatin Transitions

Cited by 287 publications

References 48 publications

Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17

Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17

Pioneer transcription factors shape the epigenetic landscape

What have single-molecule studies taught us about gene expression?

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