Endogenous Purification Reveals GREB1 as a Key Estrogen Receptor Regulatory Factor

Mohammed, Hisham; D’Santos, Clive S.; Sérandour, Aurélien A.; Ali, H. Raza; Brown, Gordon D.; Atkins, A.R.; Rueda, Oscar M.; Holmes, Kelly A.; Théodorou, Vassiliki; Robinson, James C.; Zwart, Wilbert; Saadi, Amel; Ross-Innes, Caryn S.; Chin, Suet-Feung; Menon, Suraj; Stingl, John; Palmieri, Carlo; Caldas, Carlos; Carroll, Jason S.

doi:10.1016/j.celrep.2013.01.010

Cited by 347 publications

(465 citation statements)

References 45 publications

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“…Studies in the breast cancer cell line MCF-7 show that prolonged tamoxifen exposure shifts the ERα cistrome (4-6), which consequently changes gene expression (4), possibly by changing its interactome (2,(43)(44)(45). These data are hard to translate between tissues because there are far fewer models to study ERα in endometrial cancer.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Droog

Nevedomskaya

Dackus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The DNA-binding sites of estrogen receptor α (ERα) show great plasticity under the control of hormones and endocrine therapy. Tamoxifen is a widely applied therapy in breast cancer that affects ERα interactions with coregulators and shifts the DNA-binding signature of ERα upon prolonged exposure in breast cancer. Although tamoxifen inhibits the progression of breast cancer, it increases the risk of endometrial cancer in postmenopausal women. We therefore asked whether the DNA-binding signature of ERα differs between endometrial tumors that arise in the presence or absence of tamoxifen, indicating divergent enhancer activity for tumors that develop in different endocrine milieus. Using ChIP sequencing (ChIP-seq), we compared the ERα profiles of 10 endometrial tumors from tamoxifen users with those of six endometrial tumors from nonusers and integrated these results with the transcriptomic data of 47 endometrial tumors from tamoxifen users and 64 endometrial tumors from nonusers. The ERα-binding sites in tamoxifen-associated endometrial tumors differed from those in the tumors from nonusers and had distinct underlying DNA sequences and divergent enhancer activity as marked by histone 3 containing the acetylated lysine 27 (H3K27ac). Because tamoxifen acts as an agonist in the postmenopausal endometrium, similar to estrogen in the breast, we compared ERα sites in tamoxifen-associated endometrial cancers with publicly available ERα ChIP-seq data in breast tumors and found a striking resemblance in the ERα patterns of the two tissue types. Our study highlights the divergence between endometrial tumors that arise in different hormonal conditions and shows that ERα enhancer use in human cancer differs in the presence of nonphysiological endocrine stimuli.E strogen receptor α (ERα) is a steroid hormone receptor that behaves as a transcription factor by interacting with the DNA. The DNA-binding profile (cistrome) of ERα is dependent on context and tissue type (1). The hormonal environment of the cell greatly influences this cistrome because estrogen activates ERα by binding its ligand-binding domain. Upon activation, ERα's structural conformation changes to interact with cofactors at the DNA (2) and to regulate a transcriptional program that drives cell proliferation (3). Hence, the hormonal environment modulates the ERα cistrome and thereby rewires downstream effects.Endocrine therapies, as exemplified by tamoxifen, manipulate the DNA-binding capacities of the steroid hormone receptor ERα. Tamoxifen, a small-molecule inhibitor that competes with estrogens to bind ERα, is a major endocrine agent used in treating ERα-positive breast cancer patients. Studies in the breast cancer cell line MCF-7 show that prolonged tamoxifen exposure shifts the ERα cistrome, which consequently changes gene expression (4-6).Tamoxifen is a well-known selective estrogen receptor modulator (SERM) with tissue-selective physiological action. Early reports on tamoxifen's effects on transplanted MCF-7 cells in athymic mice revealed decreased tumor c...

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Section: Discussionmentioning

confidence: 99%

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Droog

Nevedomskaya

Dackus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…GREB1 is an estrogen-responsive gene that has a largely unknown function but has been implicated in the proliferation of estrogen receptor-positive breast cancer cells (37,38). GREB1 localizes to the nucleus and has been found bound to chromatin, presumably functioning as a transcriptional coactivator of estrogen receptor-mediated transcription (39). On the basis of the characterization of JGT presented here, an interesting possibility is that hmC present in the mammalian genome, generated by the TET enzymes, can be glucosylated by GREB1.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Glucosyltransferase That Converts Hydroxymethyluracil to Base J in the Trypanosomatid Genome

Bullard

Rosa-Spiegler

Liu

et al. 2014

Journal of Biological Chemistry

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“…Homologous functions of the GREB1 gene that have been characterized in other species appear to support a putative major role in this salmonid migration trait. For example, GREB1 mediates the interaction of oestrogen receptors with other proteins and plays an important role in enhancing the ability of oestrogen to act on cells to induce transcription [53]. This link to oestrogen receptors is relevant to upstream migration timing in steelhead and other salmon, because these species migrate upstream when they are sexually maturing.…”

Section: Discussionmentioning

confidence: 99%

Genetic basis of adult migration timing in anadromous steelhead discovered through multivariate association testing

et al. 2016

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Migration traits are presumed to be complex and to involve interaction among multiple genes. We used both univariate analyses and a multivariate random forest (RF) machine learning algorithm to conduct association mapping of 15 239 single nucleotide polymorphisms (SNPs) for adult migration-timing phenotype in steelhead (Oncorhynchus mykiss). Our study focused on a model natural population of steelhead that exhibits two distinct migration-timing life histories with high levels of admixture in nature. Neutral divergence was limited between fish exhibiting summer-and winter-run migration owing to high levels of interbreeding, but a univariate mixed linear model found three SNPs from a major effect gene to be significantly associated with migration timing ( p , 0.000005) that explained 46% of trait variation. Alignment to the annotated Salmo salar genome provided evidence that all three SNPs localize within a 46 kb region overlapping GREB1-like (an oestrogen target gene) on chromosome Ssa03. Additionally, multivariate analyses with RF identified that these three SNPs plus 15 additional SNPs explained up to 60% of trait variation. These candidate SNPs may provide the ability to predict adult migration timing of steelhead to facilitate conservation management of this species, and this study demonstrates the benefit of multivariate analyses for association studies.

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Endogenous Purification Reveals GREB1 as a Key Estrogen Receptor Regulatory Factor

Cited by 347 publications

References 45 publications

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Identification of the Glucosyltransferase That Converts Hydroxymethyluracil to Base J in the Trypanosomatid Genome

Genetic basis of adult migration timing in anadromous steelhead discovered through multivariate association testing

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