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Review
. 2020 Apr 30;21(9):3177.
doi: 10.3390/ijms21093177.

Estradiol-Induced Epigenetically Mediated Mechanisms and Regulation of Gene Expression

Tamás Kovács  1 , Edina Szabó-Meleg  2 , István M Ábrahám  1
Affiliations
Review

Estradiol-Induced Epigenetically Mediated Mechanisms and Regulation of Gene Expression

Tamás Kovács et al. Int J Mol Sci. .

Abstract

Gonadal hormone 17β-estradiol (E2) and its receptors are key regulators of gene transcription by binding to estrogen responsive elements in the genome. Besides the classical genomic action, E2 regulates gene transcription via the modification of epigenetic marks on DNA and histone proteins. Depending on the reaction partner, liganded estrogen receptor (ER) promotes DNA methylation at the promoter or enhancer regions. In addition, ERs are important regulators of passive and active DNA demethylation. Furthermore, ERs cooperating with different histone modifying enzymes and chromatin remodeling complexes alter gene transcription. In this review, we survey the basic mechanisms and interactions between estrogen receptors and DNA methylation, demethylation and histone modification processes as well as chromatin remodeling complexes. The particular relevance of these mechanisms to physiological processes in memory formation, embryonic development, spermatogenesis and aging as well as in pathophysiological changes in carcinogenesis is also discussed.

Keywords: demethylation; estradiol; histone modification enzymes; histone proteins; methylation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
17β-estradiol (E2)-induced methylation mechanism. Liganded estrogen receptor (ER) binds to the estrogen responsive element (ERE) in the genome. Estrogen receptor recruits histone deacetylase 1 (HDAC), polycomb repressive complex 2 (PRC2) and enhancer of zeste homolog 2 (EZH2) (A). The HDAC removes acetyl groups from the histone 3’s 27th lysine residue (H3K27). EZH2 places three methyl groups, 3Me, on H3K27 [29] (B). DNA methyltransferase 3b (DNMT3b) recognizes the methylated H3K27 and methylates the cytosine (C) in a CpG island (C) [44].
Figure 2
Figure 2
E2-induced demethylation mechanisms. Liganded estrogen receptor (ER) binds the estrogen responsive element (ERE) in the genome. ER recruits ten-eleven translocase 2 (TET2) and thymine-DNA glycosylase (TDG). TET2 hydroxylates the methyl cytosine residue (5mC) into a hydroxymethyl cytosine (5hmC) (A1). TDG replaces the 5hmC with a naked cytosine (C) (A2). ER binds to EREs in the genome. ER recruits activation-induced cytidine deaminase (AID) and apolipoprotein B mRNA editing enzyme (APOBEC). The ER/AID/APOBEC complex deaminates a previous 5hmC into a uracil (U) (B1). TDG replaces the uracil with a naked cytosine (B2).
Figure 3
Figure 3
ERα-related epigenetic interactome. DNA methylation: DNMT3B: DNA methyltransferase 3b; EZH2: zeste homolog 2; HDAC: histone deacetylase; PRC2: polycomb complex 2; NuRD complex: nucleosome remodeling deacetylase. DNA demethylation: TET2: ten-eleven translocation enzyme 2; APOBEC: apolipoprotein B mRNA editing enzyme; AID: activation induced cytidine deaminase; CXXC5/CXXC4: CXXC-type zinc finger protein 5 and 4. Histone modification: MLL2: mixed lineage leukemia gene 2; p300: E1A Binding Protein 300; p160: steroid receptor coactivator; ERK1/2: extracellular signal-regulated kinase 1/2. Chromatin remodeling: ARID1A: AT-Rich Interaction Domain 1A; BRG1: actin dependent regulator of chromatin, subfamily a, member 4; BAF57: Actin Dependent Regulator of Chromatin, Subfamily E, Member 1; INO80: chromatin remodeling INO80 complex.
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References

    1. Compere S.J., Palmiter R.D. DNA methylation controls the inducibility of the mouse metallothionein-I gene lymphoid cells. Cell. 1981;25:233–240. doi: 10.1016/0092-8674(81)90248-8. - DOI - PubMed
    1. Holliday R., Pugh J.E. DNA modification mechanisms and gene activity during development. Science. 1975;187:226–232. doi: 10.1126/science.1111098. - DOI - PubMed
    1. Berger S.L., Kouzarides T., Shiekhattar R., Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23:781–783. doi: 10.1101/gad.1787609. - DOI - PMC - PubMed
    1. Wang G.G., Allis C.D., Chi P. Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling. Trends Mol. Med. 2007;13:373–380. doi: 10.1016/j.molmed.2007.07.004. - DOI - PMC - PubMed
    1. Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007;447:425–432. doi: 10.1038/nature05918. - DOI - PubMed

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