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

Helzer, Kyle T.; Ozers, Mary Szatkowski; Meyer, Mark B.; Benkusky, Nancy A.; Solodin, Natalia; Reese, Rebecca; Warren, Christopher L.; Pike, J. Wesley; Alarid, Elaine T.

doi:10.1128/mcb.00417-18

Cited by 19 publications

(24 citation statements)

References 99 publications

(147 reference statements)

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“…ER binding proximal to the ELP3, CTU1, and ALKBH8 genes was assessed using published ChIP-sequencing data (Helzer et al, 2018a;Swinstead et al, 2016a;Severson et al, 2018;Data Ref: Helzer et al, 2018b;Data Ref: Swinstead et al, 2016b;Data Ref: Schuurman et al, 2018). ChIP-qPCR of ER from ZR-75-1 cells was done essentially as described previously (Mohammed et al, 2015) using ER sc-543x antibody (Santa Cruz).…”

Section: Er Dna Binding Analysis By Chromatin Immunoprecipitation (Chip)mentioning

confidence: 99%

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

et al. 2019

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Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer‐associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5′UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome association remains unaltered are enriched in codons requiring U34‐modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34‐modifying enzymes and thereby controls levels of U34‐modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα‐dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone‐dependent cancers.

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Section: Er Dna Binding Analysis By Chromatin Immunoprecipitation (Chip)mentioning

confidence: 99%

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

et al. 2019

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“…18 Phosphorylated ER sites, unlike ER sites, are enriched in Grhl2 DNA-binding motifs, and estrogen treatment increases Grhl2 recruitment to former sites in MCF-7 cells. 20 However, estrogen treatment alone tended to decrease Grhl2 and its target gene expression in ovariectomized mice, indicating that estrogen is unlikely to induce Grhl2 transcription and activation in the normal ductal epithelial cells.…”

Section: Discussionmentioning

confidence: 95%

Expression of Grainyhead-like 2 in the Process of Ductal Development of Mouse Mammary Gland

Matsuoka

Suzuki

Kato

et al. 2021

J Histochem Cytochem.

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Grainyhead-like 2 (Grhl2) is a transcription factor regulating cell adhesion genes. Grhl2 acts as an epithelial–mesenchymal transition suppressor, and it is a proto-oncogene involved in estrogen-stimulated breast cancer proliferation. However, its expression during ovarian hormone–dependent mammary ductal development remains obscure. We here examined Grhl2 expression in the mammary gland of normal and steroid-replaced ovariectomized mice. Grhl2 protein signals were detected in both the mammary luminal epithelial and myoepithelial nuclei. The ratio and density of Grhl2-positive nuclei increased after the onset of puberty and progressed with age, whereas Grhl2-negative epithelial cells were detected in mature ducts. Claudin 3, claudin 4, claudin 7, and E-cadherin gene expression in the mammary gland was upregulated, and their expression was highly correlated with Grhl2 gene expression. Furthermore, Grhl2 mRNA expression and ductal lumen width were significantly increased by the combined treatment of estrogen and progesterone compared with estrogen alone. These results suggest that Grhl2 expressed in the luminal epithelial and myoepithelial cells from the early phase of ductal development, controlling the expression of cell adhesion molecules to establish functional ducts:

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“…GRHL2 expression significantly correlates with ER-positive breast cancer tumors ( Carroll et al, 2005 ; Xiang et al, 2012 ; Werner et al, 2013 ). ChIP-seq profiling of ER and phosphorylated ER at S118 (pS118-ER) occupancy sites shows a significant overlap with GRHL2 binding motifs ( Helzer et al, 2018 ; Holding et al, 2019 ). This indicates that GRHL2 occupancy in the ER binding sites potentially drives ER transcription complex.…”

Section: Pioneer Activity Of Grainyhead and Grhl Familymentioning

confidence: 99%

Spotlight on the Granules (Grainyhead-Like Proteins) – From an Evolutionary Conserved Controller of Epithelial Trait to Pioneering the Chromatin Landscape

Sundararajan

Pang

Choolani

et al. 2020

Front. Mol. Biosci.

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Among the transcription factors that are conserved across phylogeny, the grainyhead family holds vital roles in driving the epithelial cell fate. In Drosophila , the function of grainyhead ( grh ) gene is essential during developmental processes such as epithelial differentiation, tracheal tube formation, maintenance of wing and hair polarity, and epidermal barrier wound repair. Three main mammalian orthologs of grh : Grainyhead-like 1-3 (GRHL1, GRHL2, and GRHL3) are highly conserved in terms of their gene structures and functions. GRHL proteins are essentially associated with the development and maintenance of the epithelial phenotype across diverse physiological conditions such as epidermal differentiation and craniofacial development as well as pathological functions including hearing impairment and neural tube defects. More importantly, through direct chromatin binding and induction of epigenetic alterations, GRHL factors function as potent suppressors of oncogenic cellular dedifferentiation program – epithelial-mesenchymal transition and its associated tumor-promoting phenotypes such as tumor cell migration and invasion. On the contrary, GRHL factors also induce pro-tumorigenic effects such as increased migration and anchorage-independent growth in certain tumor types. Furthermore, investigations focusing on the epithelial-specific activation of grh and GRHL factors have revealed that these factors potentially act as a pioneer factor in establishing a cell-type/cell-state specific accessible chromatin landscape that is exclusive for epithelial gene transcription. In this review, we highlight the essential roles of grh and GRHL factors during embryogenesis and pathogenesis, with a special focus on its emerging pioneering function.

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

Cited by 19 publications

References 99 publications

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

Expression of Grainyhead-like 2 in the Process of Ductal Development of Mouse Mammary Gland

Spotlight on the Granules (Grainyhead-Like Proteins) – From an Evolutionary Conserved Controller of Epithelial Trait to Pioneering the Chromatin Landscape

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