Estrogen-dependent gene expression

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Homo sapiens
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Estrogens mediate their transcriptional effects through interaction with the estrogen receptors, ESR1 (also known as ER alpha) and ESR2 (ER beta). ESR1 and ESR2 share overlapping but distinct functions, with ESR1 playing the primary role in transcriptional activation in most cell types (Hah and Krauss, 2014; Haldosén et al, 2014. The receptors function as ligand-dependent dimers and can activate target genes either through direct binding to an estrogen responsive element (ERE) in the target gene promoter, or indirectly through interaction with another DNA-binding protein such as RUNX1, SP1, AP1 or NF-kappa beta (reviewed in Bai and Gust, 2009; Hah and Krause, 2014). Binding of estrogen receptors to the DNA promotes the assembly of higher order transcriptional complexes containing methyltransferases, histone acetyltransferases and other transcriptional activators, which promote transcription by establishing active chromatin marks and by recruiting general transcription factors and RNA polymerase II. ESR1- and estrogen-dependent recruitment of up to hundreds of coregulators has been demonstrated by varied co-immunoprecipitation and proteomic approaches (Kittler et al, 2013; Mohammed et al, 2013; Foulds et al, 2013; Mohammed et al, 2015; Liu et al, 2014; reviewed in Magnani and Lupien, 2014; Arnal, 2017). In some circumstances, ligand-bound receptors can also promote the assembly of a repression complex at a target gene, and in some cases, heterodimers of ESR1 and ESR2 serve as repressors of ESR1-mediated target gene activation (reviewed in Hah and Kraus, 2014; Arnal et al, 2017). Phosphorylation of the estrogen receptor also modulates its activity, and provides cross-talk between nuclear estrogen-dependent signaling and non-genomic estrogen signaling from the plasma membrane (reviewed in Anbalagan and Rowan, 2015; Halodsèn et al, 2014; Schwartz et al, 2016)

A number of recent genome wide studies highlight the breadth of the transcriptional response to estrogen. The number of predicted estrogen-dependent target genes ranges from a couple of hundred (based on microarray studies) to upwards of 10000, based on ChIP-chip or ChIP-seq (Cheung and Kraus, 2010; Kinnis and Kraus, 2008; Lin et al, 2004; Welboren et al, 2009; Ikeda et al, 2015; Lin et al, 2007; Carroll et al, 2006). Many of these predicted sites may not represent transcriptionally productive binding events, however. A study examining ESR1 binding by ChIP-seq in 20 primary breast cancers identified a core of 484 ESR-binding events that were conserved in at least 75% of ER+ tumors, which may represent a more realistic estimate (Ross-Innes et al, 2012). These studies also highlight the long-range effect of estrogen receptor-binding, with distal enhancer or promoter elements regulating the expression of many target genes, often through looping or other higher order chromatin structures (Kittler et al, 2013; reviewed in Dietz and Carroll, 2008; Liu and Cheung, 2014; Magnani and Lupien, 2014). Transcription from a number of estrogen-responsive target genes also appears to be primed by the binding of pioneering transcription factors such as FOXA1, GATA3, PBX1 among others. These factors bind to heterochromatin by virtue of their winged helix domains and promote chromatin opening, allowing subsequent recruitment of other transcription factors (reviewed in Zaret and Carroll, 2011; Fiorito et al, 2013; Arnal et al, 2017; Magnani et al, 2011)

Literature References
PubMed ID Title Journal Year
19339991 ChIP-Seq of ERalpha and RNA polymerase II defines genes differentially responding to ligands

Span, PN, Sweep, FC, van Heeringen, SJ, Welboren, WJ, Stunnenberg, HG, Janssen-Megens, EM, van Driel, MA

EMBO J. 2009
25303530 Enhancer activation requires trans-recruitment of a mega transcription factor complex

Li, W, Friedman, MJ, Krones, A, Yang, F, Rosenfeld, MG, Song, X, Oh, S, Ma, Q, Liu, Z, Merkurjev, D, Zhang, F, Ohgi, KA

Cell 2014
21151129 FOXA1 is a key determinant of estrogen receptor function and endocrine response

Ross-Innes, CS, Hurtado, A, Carroll, JS, Holmes, KA, Schmidt, D

Nat. Genet. 2011
22056668 Pioneer transcription factors: establishing competence for gene expression

Zaret, KS, Carroll, JS

Genes Dev. 2011
24071518 Estrogen receptor-mediated long-range chromatin interactions and transcription in breast cancer

Liu, MH, Cheung, E

Mol. Cell. Endocrinol. 2014
27288742 Rapid steroid hormone actions via membrane receptors

Verma, A, Schwartz, Z, Bivens, CB, Schwartz, N, Boyan, BD

Biochim. Biophys. Acta 2016
25597633 Estrogen receptor alpha phosphorylation and its functional impact in human breast cancer

Rowan, BG, Anbalagan, M

Mol. Cell. Endocrinol. 2015
23954741 Estrogen receptor beta in breast cancer

Dahlman-Wright, K, Zhao, C, Haldosén, LA

Mol. Cell. Endocrinol. 2014
15345050 Discovery of estrogen receptor alpha target genes and response elements in breast tumor cells

Kong, SL, Liu, ET, Bajic, VB, Ström, A, Bangarusamy, DK, Doray, B, Chong, A, Ramasamy, A, Tang, S, Vega, VB, Vergara, LA, Gustafsson, JA, Chan, WC, Yeo, AL, Miller, LD, Lin, CY, Thomsen, JS

Genome Biol. 2004
10873660 Promoter analysis and chromosomal mapping of human EBAG9 gene

Tsutsumi, O, Sato, M, Inazawa, J, Emi, M, Tsuneizumi, M, Ikeda, K, Tsuchiya, F, Muramatsu, M, Inoue, S, Imoto, I

Biochem. Biophys. Res. Commun. 2000
23192763 Cooperating transcription factors mediate the function of estrogen receptor

Hurtado, A, Fiorito, E, Katika, MR

Chromosoma 2013
18301785 A global view of transcriptional regulation by nuclear receptors: gene expression, factor localization, and DNA sequence analysis

Kraus, WL, Kininis, M

Nucl Recept Signal 2008
23850489 Proteomic analysis of coregulators bound to ERα on DNA and nucleosomes reveals coregulator dynamics

Tsai, SY, Malovannaya, A, Tsai, MJ, Feng, Q, Qin, J, Gates, LA, O'Malley, BW, Bailey, S, Bajaj, A, Foulds, CE, Callaway, CG, Edwards, DP, Hunsaker, TL, Hamilton, RA, Zhang, Z, Lonard, DM, Chan, D, Ding, C, Li, C

Mol. Cell 2013
20148673 Genomic analyses of hormone signaling and gene regulation

Kraus, WL, Cheung, E

Annu. Rev. Physiol. 2010
18377699 Interrogating the genome to understand oestrogen-receptor-mediated transcription

Carroll, JS, Dietz, SC

Expert Rev Mol Med 2008
28539435 Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications

Katzenellenbogen, B, Chambon, P, Flouriot, G, Métivier, R, Henrion, D, Katzenellenbogen, J, Arnal, JF, Lenfant, F, Gourdy, P, Fontaine, C, Adlanmerini, M

Physiol. Rev. 2017
23684889 Chromatin and epigenetic determinants of estrogen receptor alpha (ESR1) signaling

Magnani, L, Lupien, M

Mol. Cell. Endocrinol. 2014
17013392 Genome-wide analysis of estrogen receptor binding sites

Bekiranov, S, Hall, GF, Li, W, Fertuck, KC, Geistlinger, TR, Sementchenko, V, Liu, XS, Brodsky, AS, Meyer, CA, Silver, PA, Fox, EA, Brown, M, Wang, Q, Keeton, EK, Eeckhoute, J, Song, J, Gingeras, TR, Carroll, JS

Nat. Genet. 2006
17510434 Novel estrogen receptor-alpha binding sites and estradiol target genes identified by chromatin immunoprecipitation cloning in breast cancer

Bulun, SE, Huang, CC, Lin, Z, Reierstad, S

Cancer Res. 2007
19274700 Breast cancer, estrogen receptor and ligands

Bai, Z, Gust, R

Arch. Pharm. (Weinheim) 2009
23810978 Hormone-regulated transcriptomes: lessons learned from estrogen signaling pathways in breast cancer cells

Kraus, WL, Hah, N

Mol. Cell. Endocrinol. 2014
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