Network analysis of ChIP-seq data by VULCAN identifies GRHL2 as a key co-regulator of ERa in luminal breast cancer

An, Hong‐Mei; Giorgi, Federico M.; Donnelly, Amanda; Ae, Cullen; Nagarajan, Sankari; Selth, Luke A.; Markowetz, Florian

doi:10.1101/266908

Cited by 3 publications

(2 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GRHL2 occupancy was also found to increase upon E2 treatment at these overlapping sites but not at GRHL2 sites devoid of pS118-ER. This finding is supported by a recent preprint by Holding et al, which reported a genomewide increase of GRHL2 binding in the presence of E2 and many of the E2-induced GRHL2 occupancy sites overlapped ER occupancy sites (76). GRHL2 is a transcription factor involved in embryonic development, and it has been implicated as both a tumor suppressor and an oncogene depending on the cellular context (77,78).…”

Section: Discussionmentioning

confidence: 55%

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

Helzer

Ozers

Meyer

et al. 2019

Molecular and Cellular Biology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 55%

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

Helzer

Ozers

Meyer

et al. 2019

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…In trying to make sense of the data we had, we tested alternative methods to integrate it and to increase the power of our genome‐wide experiments, none of which conclusively reproduced the reported cycling. These attempts were not without some success: one of the methods would go on to be published separately . However, none of these ideas definitively confirmed the cycling result we were looking for.…”

Section: Squinting At Datamentioning

confidence: 95%

Novelty in science should not come at the cost of reproducibility

Holding

2019

The FEBS Journal

Self Cite

View full text Add to dashboard Cite

The pressures of a scientific career can end up incentivising an all‐or‐nothing approach to cross the finish line first. While competition can be healthy and drives innovation, the current system fails to encourage scientists to work reproducibility. This sometimes leaves those individuals who come second to correct mistakes in published research without being rewarded. Instead, we need a culture that rewards reproducibility and holds it as important as the novelty of the result. Here, I draw on my own journey in the oestrogen receptor research field to highlight this and suggest ways for the ‘first past the post’ culture to be challenged.

show abstract

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

Holding

Cullen

Markowetz

2018

eLife

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Network analysis of ChIP-seq data by VULCAN identifies GRHL2 as a key co-regulator of ERa in luminal breast cancer

Abstract: Background Estrogen Receptor-alpha (ER) is the main driver of~75% of all breast cancers.

Cited by 3 publications

References 59 publications

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

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

Novelty in science should not come at the cost of reproducibility

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

Contact Info

Product

Resources

About