scholarly journals Sufficiency analysis of estrogen responsive enhancers using synthetic activators

2019 ◽  
Vol 2 (5) ◽  
pp. e201900497 ◽  
Author(s):  
Matthew Ginley-Hidinger ◽  
Julia B Carleton ◽  
Adriana C Rodriguez ◽  
Kristofer C Berrett ◽  
Jason Gertz
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor ◽  
Rna Polymerase Ii ◽  
Binding Sites ◽  
Estrogen Receptor Α ◽  
Control Gene ◽  
Regulatory Regions ◽  
Control Gene Expression ◽  
Highly Correlated ◽  
Independent Effects

Multiple regulatory regions bound by the same transcription factor have been shown to simultaneously control a single gene’s expression. However, it remains unclear how these regulatory regions combine to regulate transcription. Here, we test the sufficiency of promoter-distal estrogen receptor α-binding sites (ERBSs) for activating gene expression by recruiting synthetic activators in the absence of estrogens. Targeting either dCas9-VP16(10x) or dCas9-p300(core) to ERBS induces H3K27ac and activates nearby expression in a manner similar to an estrogen induction, with dCas9-VP16(10x) acting as a stronger activator. The sufficiency of individual ERBSs is highly correlated with their necessity, indicating an inherent activation potential that is associated with the binding of RNA polymerase II and several transcription factors. By targeting ERBS combinations, we found that ERBSs work independently to control gene expression when bound by synthetic activators. The sufficiency results contrast necessity assays that show synergy between these ERBSs, suggesting that synergy occurs between ERBSs in terms of activator recruitment, whereas directly recruiting activators leads to independent effects on gene expression.

scholarly journals Sufficiency analysis of estrogen responsive enhancers using synthetic activators

2018 ◽  
Author(s):  
Matthew Ginley-Hidinger ◽  
Julia B. Carleton ◽  
Adriana C. Rodriguez ◽  
Kristofer C. Berrett ◽  
Jason Gertz
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor ◽  
Rna Polymerase Ii ◽  
Binding Sites ◽  
Estrogen Receptor Α ◽  
Control Gene ◽  
Regulatory Regions ◽  
Control Gene Expression ◽  
Highly Correlated ◽  
Independent Effects

AbstractMultiple regulatory regions bound by the same transcription factor have been shown to simultaneously control a single gene’s expression. However, it remains unclear how these regulatory regions combine to regulate transcription. Here we test the sufficiency of promoter-distal estrogen receptor α (ER)-binding sites (ERBS) for activating gene expression by recruiting synthetic activators in the absence of estrogens. Targeting either dCas9-VP16(10x) or dCas9-p300(core) to ERBS induces H3K27ac and activates nearby expression in a manner similar to an estrogen induction, with dCas9-VP16(10x) acting as a stronger activator. The sufficiency of individual ERBS is highly correlated with their necessity, indicating an inherent activation potential that is associated with the binding of RNA polymerase II and several transcription factors. By targeting ERBS combinations, we found that ERBS work independently to control gene expression when bound by synthetic activators. The sufficiency results contrast necessity assays that show synergy between these ERBS, suggesting that synergy occurs between ERBS in terms of activator recruitment, whereas directly recruiting activators leads to independent effects on gene expression.

scholarly journals Enhancers predominantly regulate gene expression in vivo via transcription initiation

2019 ◽  
Author(s):  
Martin S. C. Larke ◽  
Takayuki Nojima ◽  
Jelena Telenius ◽  
Jacqueline A. Sharpe ◽  
Jacqueline A. Sloane-Stanley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Transcription Initiation ◽  
Genetically Engineered ◽  
Control Gene ◽  
Transcriptional Initiation ◽  
Pol Ii ◽  
Rna Molecules ◽  
Control Gene Expression

ABSTRACTGene transcription occurs via a cycle of linked events including initiation, promoter proximal pausing and elongation of RNA polymerase II (Pol II). A key question is how do transcriptional enhancers influence these events to control gene expression? Here we have used a new approach to quantify transcriptional initiation and pausing in vivo, while simultaneously identifying transcription start sites (TSSs) and pause-sites (TPSs) from single RNA molecules. When analyzed in parallel with nascent RNA-seq, these data show that differential gene expression is achieved predominantly via changes in transcription initiation rather than Pol II pausing. Using genetically engineered mouse models deleted for specific enhancers we show that these elements control gene expression via Pol II recruitment and/or initiation rather than via promoter proximal pause release. Together, our data show that enhancers, in general, control gene expression predominantly by Pol II recruitment and initiation rather than via pausing.

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.

LEC1 (NF-YB9) directly interacts with LEC2 to control gene expression in seed

2018 ◽  
Vol 1861 (5) ◽  
pp. 443-450 ◽  
Author(s):  
C. Boulard ◽  
J. Thévenin ◽  
O. Tranquet ◽  
V. Laporte ◽  
L. Lepiniec ◽  
...  
Keyword(s):  
Gene Expression ◽  
Control Gene ◽  
Control Gene Expression

scholarly journals Nonhistone Proteins Control Gene Expression in Reconstituted Chromatin

1974 ◽  
Vol 71 (12) ◽  
pp. 5057-5061 ◽  
Author(s):  
T. Barrett ◽  
D. Maryanka ◽  
P. H. Hamlyn ◽  
H. J. Gould
Keyword(s):  
Gene Expression ◽  
Control Gene ◽  
Nonhistone Proteins ◽  
Control Gene Expression

scholarly journals Loading-related regulation of gene expression in bone in the contexts of estrogen deficiency, lack of estrogen receptor α and disuse

Bone ◽  
2010 ◽  
Vol 46 (3) ◽  
pp. 628-642 ◽  
Author(s):  
Gul Zaman ◽  
Leanne K. Saxon ◽  
Andrew Sunters ◽  
Helen Hilton ◽  
Peter Underhill ◽  
...  
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor ◽  
Regulation Of Gene Expression ◽  
Estrogen Receptor Α ◽  
Estrogen Deficiency

scholarly journals Repression of ESR1 through Actions of Estrogen Receptor Alpha and Sin3A at the Proximal Promoter

2009 ◽  
Vol 29 (18) ◽  
pp. 4949-4958 ◽  
Author(s):  
Stephanie J. Ellison-Zelski ◽  
Natalia M. Solodin ◽  
Elaine T. Alarid
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Rna Polymerase Ii ◽  
Transcriptional Repression ◽  
Estrogen Receptor Alpha ◽  
Proximal Promoter ◽  
Receptor Alpha ◽  
Expression Of Genes ◽  
Activation Of Transcription

ABSTRACT Gene expression results from the coordinated actions of transcription factor proteins and coregulators. Estrogen receptor alpha (ERα) is a ligand-activated transcription factor that can both activate and repress the expression of genes. Activation of transcription by estrogen-bound ERα has been studied in detail, as has antagonist-induced repression, such as that which occurs by tamoxifen. How estrogen-bound ERα represses gene transcription remains unclear. In this report, we identify a new mechanism of estrogen-induced transcriptional repression by using the ERα gene, ESR1. Upon estrogen treatment, ERα is recruited to two sites on ESR1, one distal (ENH1) and the other at the proximal (A) promoter. Coactivator proteins, namely, p300 and AIB1, are found at both ERα-binding sites. However, recruitment of the Sin3A repressor, loss of RNA polymerase II, and changes in histone modifications occur only at the A promoter. Reduction of Sin3A expression by RNA interference specifically inhibits estrogen-induced repression of ESR1. Furthermore, an estrogen-responsive interaction between Sin3A and ERα is identified. These data support a model of repression wherein actions of ERα and Sin3A at the proximal promoter can overcome activating signals at distal or proximal sites and ultimately decrease gene expression.

scholarly journals A Quantitative Optogenetic Tool to Control Gene Expression during Embryonic Development

2021 ◽  
Vol 120 (3) ◽  
pp. 354a
Author(s):  
Anand P. Singh ◽  
Ping Wu ◽  
Eric F. Wieschaus ◽  
Jared E. Toettcher ◽  
Thomas Gregor
Keyword(s):  
Gene Expression ◽  
Embryonic Development ◽  
Control Gene ◽  
Control Gene Expression

scholarly journals The Phosphorylated Estrogen Receptor α (ER) Cistrome Identifies a Subset of Active Enhancers Enriched for Direct ER-DNA Binding and the Transcription Factor GRHL2

2018 ◽  
Vol 39 (3) ◽  
Author(s):  
Kyle T. Helzer ◽  
Mary Szatkowski Ozers ◽  
Mark B. Meyer ◽  
Nancy A. Benkusky ◽  
Natalia Solodin ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Transcription Factor ◽  
Dna Binding ◽  
Protein Interactions ◽  
Posttranslational Modifications ◽  
Binding Sites ◽  
Protein Function ◽  
Estrogen Receptor Α ◽  
Binding Activity

ABSTRACT Posttranslational modifications are key regulators of protein function, providing cues that can alter protein interactions and cellular location. Phosphorylation of estrogen receptor α (ER) at serine 118 (pS118-ER) occurs in response to multiple stimuli and is involved in modulating ER-dependent gene transcription. While the cistrome of ER is well established, surprisingly little is understood about how phosphorylation impacts ER-DNA binding activity. To define the pS118-ER cistrome, chromatin immunoprecipitation sequencing was performed on pS118-ER and ER in MCF-7 cells treated with estrogen. pS118-ER occupied a subset of ER binding sites which were associated with an active enhancer mark, acetylated H3K27. Unlike ER, pS118-ER sites were enriched in GRHL2 DNA binding motifs, and estrogen treatment increased GRHL2 recruitment to sites occupied by pS118-ER. Additionally, pS118-ER occupancy sites showed greater enrichment of full-length estrogen response elements relative to ER sites. In an in vitro DNA binding array of genomic binding sites, pS118-ER was more commonly associated with direct DNA binding events than indirect binding events. These results indicate that phosphorylation of ER at serine 118 promotes direct DNA binding at active enhancers and is a distinguishing mark for associated transcription factor complexes on chromatin.

G-protein Coupled Estrogen Receptor Expression in Growth Hormone Secreting and Non-Functioning Adenomas

2020 ◽  
Author(s):  
Hande Mefkure Ozkaya ◽  
Muge Sayitoglu ◽  
Nil Comunoglu ◽  
Eda Sun ◽  
Fatma Ela Keskin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor ◽  
Protein Expression ◽  
G Protein ◽  
Estrogen Receptor Α ◽  
Receptor Expression ◽  
Positive Correlation ◽  
Polymerase Chain ◽  
G Protein Coupled ◽  
Transforming Gene

Abstract Purpose To evaluate the expression of G-protein coupled estrogen receptor (GPER1), aromatase, estrogen receptor α (ERα), estrogen receptor β (ERβ), pituitary tumor transforming gene (PTTG), and fibroblast growth factor 2 (FGF2) in GH-secreting and non-functioning adenomas (NFA). Methods Thirty patients with acromegaly and 27 patients with NFA were included. Gene expression was determined via quantitative reverse transcription polymerase chain reaction (QRT-PCR). Protein expression was determined via immunohistochemistry. Results There was no difference, in terms of gene expression of aromatase, ERα, PTTG, and FGF2 between the two groups (p>0.05 for all). ERβ gene expression was higher and GPER1 gene expression was lower in GH-secreting adenomas than NFAs (p<0.05 for all). Aromatase and ERβ protein expression was higher in GH-secreting adenomas than NFAs (p=0.01). None of the tumors expressed ERα. GPER1 expression was detected in 62.2% of the GH-secreting adenomas and 45% of NFAs. There was no difference in terms of GPER1, PTTG, FGF2 H scores between the two groups (p>0.05 for all). GPER1 gene expression was positively correlated to ERα, ERβ, PTTG, and FGF2 gene expression (p<0.05 for all). There was a positive correlation between aromatase and GPER1 protein expression (r=0.31; p=0.04). Conclusions GPER1 is expressed at both gene and protein level in a substantial portion of GH-secreting adenomas and NFAs. The finding of a positive correlation between GPER1 and ERα, ERβ, PTTG, and FGF2 gene expression and aromatase and GPER1 protein expression suggests GPER1 along with aromatase and classical ERs might mediate the effects of estrogen through upregulation of PTTG and FGF2.

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