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GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202622 | GEO | 2022/05/19

REPOSITORIES: GEO

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GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression [RNA-seq]

Project description:Phosphorylation of estrogen receptor α (ER) at serine 118 (pS118-ER) is induced by estrogen and is the most abundant post-translational mark associated with a transcriptionally active receptor. Cistromic analysis of pS118-ER from our group found enrichment of the GRHL2 motif near pS118-ER binding sites. In this report we use cistromic and transcriptomic analyses to interrogate the relationship between GRHL2 and pS118-ER. We found that GRHL2 is bound to chromatin at pS118-ER/GRHL2 co-occupancy sites prior to ligand treatment, and GRHL2 binding is required for maximal pS118-ER recruitment. pS118-ER/GRHL2 co-occupancy sites were enriched at active enhancers marked by H3K27ac and H3K4me1, along with FOXA1 and p300. Transcriptomic analysis yielded four subsets of ER/GRHL2 co-regulated genes revealing that GRHL2 can both enhance and antagonize E2-mediated ER transcriptional activity. Gene ontology analysis identified several coregulated genes involved in cell migration. Accordingly, knockdown of GRHL2 combined with estrogen treatment resulted in increased cell migration but no change in proliferation. These results support a model in which GRHL2 binds to select enhancers and facilitates pS118-ER recruitment to chromatin which then results in differential activation and repression of genes that control ER-positive breast cancer cell migration.

2022-05-19 | GSE202621 | GEO

GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression[ChIP-seq]

2022-05-19 | GSE202620 | GEO

GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression [Cut&Run]

2022-05-19 | GSE202619 | GEO

GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression

Project description:GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression

| PRJNA836788 | ENA

GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression [RNA-seq]

Project description:GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression [RNA-seq]

| PRJNA836798 | ENA

GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression [Cut&Run]

Project description:GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression [Cut&Run]

| PRJNA836800 | ENA

GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression[ChIP-seq]

Project description:GRHL2 enhances phosphorylated estrogen receptor DNA binding and regulates ER-mediated transcriptional activation and repression[ChIP-seq]

| PRJNA836799 | ENA

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

Project description:Posttranslational modifications are key regulators of protein function, providing cues that can alter protein interactions and cellular location. Phosphorylation of estrogen receptor ? (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.

| S-EPMC6336141 | biostudies-literature

Analysis of the Phosphorylated Estrogen Receptor-α Cistrome Reveals Association with Direct ER-DNA Binding and the Transcription Factor GRHL2

Project description:Phosphorylation of the estrogen receptor-α (ER) at serine 118 (pS118-ER) is involved in modulating ER-dependent gene transcription and recruitment of ER to certain gene promoters. While the effects of pS118 on ER-DNA interactions have been investigated at specific sites, the genome-wide binding profile (cistrome) of pS118-ER remains to be studied. To characterize the pS118-ER cistrome, ChIP-seq was performed on pS118-ER and pan-ER in MCF-7 cells. A subset of ER sites was occupied by pS118-ER and these sites were associated with the active enhancer mark H3K27ac. Additionally, pS118-ER sites were found to be enriched in the DNA binding motif for GRHL2 as well as the estrogen response element relative to all ER sites. Utilizing a DNA binding microarray, pS118-ER was found to be more commonly associated with direct DNA binding events compared to indirect binding events. These results suggest a role for pS118-ER at active enhancers and as a regulator of direct ER-DNA interactions.

2018-12-11 | GSE117569 | GEO

A kinetic model identifies phosphorylated estrogen receptor-? (ER?) as a critical regulator of ER? dynamics in breast cancer.

Project description:Receptor levels are a key mechanism by which cells regulate their response to stimuli. The levels of estrogen receptor-? (ER?) impact breast cancer cell proliferation and are used to predict prognosis and sensitivity to endocrine therapy. Despite the clinical application of this information, it remains unclear how different cellular processes interact as a system to control ER? levels. To address this question, experimental results from the ER?-positive human breast cancer cell line (MCF-7) treated with 17-?-estradiol or vehicle control were used to develop a mass-action kinetic model of ER? regulation. Model analysis determined that RNA dynamics could be captured through phosphorylated ER? (pER?)-dependent feedback on transcription. Experimental analysis confirmed that pER?-S118 binds to the estrogen receptor-1 (ESR1) promoter, suggesting that pER? can feedback on ESR1 transcription. Protein dynamics required a separate mechanism in which the degradation rate for pER? was 8.3-fold higher than nonphosphorylated ER?. Using a model with both mechanisms, the root mean square error was 0.078. Sensitivity analysis of this combined model determined that while multiple mechanisms regulate ER? levels, pER?-dependent feedback elicited the strongest effect. Combined, our computational and experimental results identify phosphorylation of ER? as a critical decision point that coordinates the cellular circuitry to regulate ER? levels.

| S-EPMC4415015 | biostudies-literature

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