scholarly journals Genome-wide Estrogen Receptor-α activation is sustained, not cyclical

2018 ◽  
Author(s):  
Andrew N Holding ◽  
Amy E Cullen ◽  
Florian Markowetz
Keyword(s):  
Estrogen Receptor ◽  
Binding Affinity ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Genome Wide ◽  
Main Driver ◽  
Precise Quantification ◽  
Key Driver ◽  
Parallel Factor

AbstractEstrogen Receptor-α (ER) is the key driver of 75% of all breast cancers. Upon stimulation by its ligand estra-2-diol, ER forms a transcriptionally active complex binding chromatin. Previous studies have reported that ER binding follows a cyclical binding pattern with a periodicity of 90 minutes. However, these studies have been limited to individual ER target genes and most were done without replicates. Thus, the robustness and generality of ER cycling are not well understood.Here we present a comprehensive genome-wide analysis of the time dependence of ER binding affinity up to 90 minutes after activation, based on 6 replicates at 10 time points using our previously reported method for precise quantification of binding, Parallel-Factor ChIP-seq (pfChIP-seq). In contrast to previously described cyclical binding, our approach identifies a unidirectional sustained increase in ER binding affinity, as well as a class of estra-2-diol independent binding sites. Our results are corrob-orated by a quantitative re-analysis of data from multiple independent studies.Our new model reconciles the results of multiple conflicting studies into the activation of ER at the TFF1 promoter. We provide a detailed understanding of ER’s response to estra-2-diol in the context of the receptor’s fundamental role as both the main driver and therapeutic target of breast cancer.

scholarly journals Genome-wide Estrogen Receptor-α activation is sustained, not cyclical

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Andrew N Holding ◽  
Amy E Cullen ◽  
Florian Markowetz
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Genome Wide ◽  
Cyclical Pattern ◽  
Precise Quantification ◽  
Parallel Factor ◽  
Sustained Increase

Estrogen Receptor-alpha (ER) drives 75% of breast cancers. Stimulation of the ER by estra-2-diol forms a transcriptionally-active chromatin-bound complex. Previous studies reported that ER binding follows a cyclical pattern. However, most studies have been limited to individual ER target genes and without replicates. Thus, the robustness and generality of ER cycling are not well understood. We present a comprehensive genome-wide analysis of the ER after activation, based on 6 replicates at 10 time-points, using our method for precise quantification of binding, Parallel-Factor ChIP-seq. In contrast to previous studies, we identified a sustained increase in affinity, alongside a class of estra-2-diol independent binding sites. Our results are corroborated by quantitative re-analysis of multiple independent studies. Our new model reconciles the conflicting studies into the ER at the TFF1 promoter and provides a detailed understanding in the context of the ER’s role as both the driver and therapeutic target of breast cancer.

scholarly journals Epigenetics meets estrogen receptor: regulation of estrogen receptor by direct lysine methylation

2009 ◽  
Vol 16 (2) ◽  
pp. 319-323 ◽  
Author(s):  
Qun Zhou ◽  
Patrick G Shaw ◽  
Nancy E Davidson
Keyword(s):  
Estrogen Receptor ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Nuclear Hormone Receptor ◽  
Cellular Growth ◽  
Breast Cancers ◽  
Lysine Methylation ◽  
Estrogen Response

The nuclear hormone receptor estrogen receptor α (ERα) promotes cellular growth through ligand-dependent activation of specific target genes, a process which is targeted in the treatment of ERα-expressing breast cancers. ERα activity is regulated at the protein level by post-translational modifications including phosphorylation and acetylation. A study now shows that ERα can also be directly methylated at lysine 302 (K302) by SET7, a histone methyltransferase that is known to monomethylate H3K4 and is associated with transcriptional activation. It was shown that K302 methylation stabilizes ERα protein and is suggested to increase sensitivity of ERα to estrogens, enhancing transcription of estrogen response elements. Furthermore, SET7 methylation of K302 is enhanced by a breast cancer-associated mutation at K303 (K303R) in vitro. These findings provide an additional mechanism of SET7 mediated transcriptional activation, as well as potential insight into the complex regulation of ERα stability and ligand sensitivity.

scholarly journals The estrogen receptor-α-induced microRNA signature regulates itself and its transcriptional response

2009 ◽  
Vol 106 (37) ◽  
pp. 15732-15737 ◽  
Author(s):  
Leandro Castellano ◽  
Georgios Giamas ◽  
Jimmy Jacob ◽  
R. Charles Coombes ◽  
Walter Lucchesi ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Target Genes ◽  
Transcriptional Response ◽  
Regulatory System ◽  
Protein Translation ◽  
Mature Mirnas ◽  
Estrogen Receptor Α ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Wide Range

Following estrogenic activation, the estrogen receptor-α (ERα) directly regulates the transcription of target genes via DNA binding. MicroRNAs (miRNAs) modulated by ERα have the potential to fine tune these regulatory systems and also provide an alternate mechanism that could impact on estrogen-dependent developmental and pathological systems. Through a microarray approach, we identify the subset of microRNAs (miRNAs) modulated by ERα, which include upregulation of miRNAs derived from the processing of the paralogous primary transcripts (pri-) mir-17–92 and mir-106a-363. Characterization of the mir-17–92 locus confirms that the ERα target protein c-MYC binds its promoter in an estrogen-dependent manner. We observe that levels of pri-mir-17–92 increase earlier than the mature miRNAs derived from it, implicating precursor cleavage modulation after transcription. Pri-mir-17–92 is immediately cleaved by DROSHA to pre-miR-18a, indicating that its regulation occurs during the formation of the mature molecule from the precursor. The clinical implications of this novel regulatory system were confirmed by demonstrating that pre-miR-18a was significantly upregulated in ERα-positive compared to ERα-negative breast cancers. Mechanistically, miRNAs derived from these paralogous pri-miRNAs (miR-18a, miR-19b, and miR-20b) target and downregulate ERα, while a subset of pri-miRNA-derived miRNAs inhibit protein translation of the ERα transcriptional p160 coactivator, AIB1. Therefore, different subsets of miRNAs identified act as part of a negative autoregulatory feedback loop. We propose that ERα, c-MYC, and miRNA transcriptional programs invoke a sophisticated network of interactions able to provide the wide range of coordinated cellular responses to estrogen.

scholarly journals Genomic actions of estrogen receptor α: what are the targets and how are they regulated?

2009 ◽  
Vol 16 (4) ◽  
pp. 1073-1089 ◽  
Author(s):  
Willem-Jan Welboren ◽  
Fred C G J Sweep ◽  
Paul N Span ◽  
Hendrik G Stunnenberg
Keyword(s):  
Estrogen Receptor ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Post Translational Modifications ◽  
Technological Advances ◽  
Genome Wide ◽  
Complex Process ◽  
A Genome ◽  
Wide Scale ◽  
Different Levels

The estrogen receptor α (ERα) is a ligand-dependent transcription factor that regulates a large number of genes in many different target tissues and is important in the development and progression of breast cancer. ERα-mediated transcription is a complex process regulated at many different levels. The interplay between ligand, receptor, DNA sequence, cofactors, chromatin context, and post-translational modifications culminates in transcriptional regulation by ERα. Recent technological advances have allowed the identification of ERα target genes on a genome-wide scale. In this review, we provide an overview of the progress made in our understanding of the different levels of regulation mediated by ERα. We discuss the recent advances in the identification of the ERα-binding sites and target gene network and their clinical applications.

scholarly journals PARP7 and Mono-ADP-Ribosylation Negatively Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 623
Author(s):  
Marit Rasmussen ◽  
Susanna Tan ◽  
Venkata S. Somisetty ◽  
David Hutin ◽  
Ninni Elise Olafsen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Protein Modification ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Transactivation Domain ◽  
Adp Ribosylation ◽  
Protein Levels ◽  
17Β Estradiol ◽  
Mcf 7

ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.

scholarly journals AKT Alters Genome-Wide Estrogen Receptor α Binding and Impacts Estrogen Signaling in Breast Cancer

2008 ◽  
Vol 28 (24) ◽  
pp. 7487-7503 ◽  
Author(s):  
Poornima Bhat-Nakshatri ◽  
Guohua Wang ◽  
Hitesh Appaiah ◽  
Nikhil Luktuke ◽  
Jason S. Carroll ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Binding Sites ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Primary Tumors ◽  
Genome Wide ◽  
Extracellular Signal

ABSTRACT Estrogen regulates several biological processes through estrogen receptor α (ERα) and ERβ. ERα-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60% overlap. In both cell types, ∼40% of estrogen-regulated genes associate with ERα binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.

scholarly journals Differential Regulation of Estrogen-Inducible Proteolysis and Transcription by the Estrogen Receptor α N Terminus

2005 ◽  
Vol 25 (13) ◽  
pp. 5417-5428 ◽  
Author(s):  
Christopher C. Valley ◽  
Raphaël Métivier ◽  
Natalia M. Solodin ◽  
Amy M. Fowler ◽  
Mara T. Mashek ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Transactivation Domain ◽  
Related Factors ◽  
Additional Element ◽  
Transactivation Domains ◽  
Ubiquitin Proteasome ◽  
Transcriptional Complex

ABSTRACT The ubiquitin-proteasome pathway has emerged as an important regulatory mechanism governing the activity of several transcription factors. While estrogen receptor α (ERα) is also subjected to rapid ubiquitin-proteasome degradation, the relationship between proteolysis and transcriptional regulation is incompletely understood. Based on studies primarily focusing on the C-terminal ligand-binding and AF-2 transactivation domains, an assembly of an active transcriptional complex has been proposed to signal ERα proteolysis that is in turn necessary for its transcriptional activity. Here, we investigated the role of other regions of ERα and identified S118 within the N-terminal AF-1 transactivation domain as an additional element for regulating estrogen-induced ubiquitination and degradation of ERα. Significantly, different S118 mutants revealed that degradation and transcriptional activity of ERα are mechanistically separable functions of ERα. We find that proteolysis of ERα correlates with the ability of ERα mutants to recruit specific ubiquitin ligases regardless of the recruitment of other transcription-related factors to endogenous model target genes. Thus, our findings indicate that the AF-1 domain performs a previously unrecognized and important role in controlling ligand-induced receptor degradation which permits the uncoupling of estrogen-regulated ERα proteolysis and transcription.

Calcineurin regulates the stability and activity of estrogen receptor α

2021 ◽  
Vol 118 (44) ◽  
pp. e2114258118
Author(s):  
Takahiro Masaki ◽  
Makoto Habara ◽  
Yuki Sato ◽  
Takahiro Goshima ◽  
Keisuke Maeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
The Stability ◽  
Positive Breast Cancer

Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to β-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118. Finally, the expression of the calcineurin A–α gene (PPP3CA) was associated with poor prognosis in ER-α–positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α–positive breast cancer.

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