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  1. Article ; Online: Multiple tissue-specific epigenetic alterations regulate persistent gene expression changes following developmental DES exposure in mouse reproductive tissues.

    Jefferson, Tanner B / Wang, Tianyuan / Jefferson, Wendy N / Li, Yin / Hamilton, Katherine J / Wade, Paul A / Williams, Carmen J / Korach, Kenneth S

    Epigenetics

    2022  Volume 18, Issue 1, Page(s) 2139986

    Abstract: Clinically, developmental exposure to the endocrine disrupting chemical, diethylstilboestrol (DES), results in long-term male and female infertility. Experimentally, developmental exposure to DES results in abnormal reproductive tract phenotypes in male ... ...

    Abstract Clinically, developmental exposure to the endocrine disrupting chemical, diethylstilboestrol (DES), results in long-term male and female infertility. Experimentally, developmental exposure to DES results in abnormal reproductive tract phenotypes in male and female mice. Previously, we reported that neonatal DES exposure causes ERα-mediated aberrations in the transcriptome and in DNA methylation in seminal vesicles (SVs) of adult mice. However, only a subset of DES-altered genes could be explained by changes in DNA methylation. We hypothesized that alterations in histone modification may also contribute to the altered transcriptome during SV development. To test this idea, we performed a series of genome-wide analyses of mouse SVs at pubertal and adult developmental stages in control and DES-exposed wild-type and ERα knockout mice. Neonatal DES exposure altered ERα-mediated mRNA and lncRNA expression in adult SV, including genes encoding chromatin-modifying proteins that can impact histone H3K27ac modification. H3K27ac patterns, particularly at enhancers, and DNA methylation were reprogrammed over time during normal SV development and after DES exposure. Some of these reprogramming changes were ERα-dependent, but others were ERα-independent. A substantial number of DES-altered genes had differential H3K27ac peaks at nearby enhancers. Comparison of gene expression changes, H3K27ac marks and DNA methylation marks between adult SV and adult uterine tissue from ovariectomized mice neonatally exposed to DES revealed that most of the epigenetic changes and altered genes were distinct in the two tissues. These findings indicate that the effects of developmental DES exposure cause reprogramming of reproductive tract tissue differentiation through multiple epigenetic mechanisms.
    MeSH term(s) Animals ; Mice ; Male ; Female ; Diethylstilbestrol/pharmacology ; Estrogen Receptor alpha/genetics ; DNA Methylation ; Genome-Wide Association Study ; Epigenesis, Genetic ; Gene Expression
    Chemical Substances Diethylstilbestrol (731DCA35BT) ; Estrogen Receptor alpha
    Language English
    Publishing date 2022-11-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ISSN 1559-2308
    ISSN (online) 1559-2308
    DOI 10.1080/15592294.2022.2139986
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: ESR1 Mutations Associated With Estrogen Insensitivity Syndrome Change Conformation of Ligand-Receptor Complex and Altered Transcriptome Profile.

    Li, Yin / Hamilton, Katherine J / Perera, Lalith / Wang, Tianyuan / Gruzdev, Artiom / Jefferson, Tanner B / Zhang, Austin X / Mathura, Emilie / Gerrish, Kevin E / Wharey, Laura / Martin, Negin P / Li, Jian-Liang / Korach, Kenneth S

    Endocrinology

    2020  Volume 161, Issue 6

    Abstract: Estrogen insensitivity syndrome (EIS) arises from rare mutations in estrogen receptor-α (ERα, encoded by ESR1 gene) resulting in the inability of estrogen to exert its biological effects. Due to its rarity, mutations in ESR1 gene and the underlying ... ...

    Abstract Estrogen insensitivity syndrome (EIS) arises from rare mutations in estrogen receptor-α (ERα, encoded by ESR1 gene) resulting in the inability of estrogen to exert its biological effects. Due to its rarity, mutations in ESR1 gene and the underlying molecular mechanisms of EIS have not been thoroughly studied. Here, we investigate known ESR1 mutants, Q375H and R394H, associated with EIS patients using in vitro and in vivo systems. Comparison of the transcriptome and deoxyribonucleic acid methylome from stable cell lines of both Q375H and R394H clinical mutants shows a differential profile compared with wild-type ERα, resulting in loss of estrogen responsiveness. Molecular dynamic simulation shows that both ESR1 mutations change the ERα conformation of the ligand-receptor complexes. Furthermore, we generated a mouse model Esr1-Q harboring the human mutation using CRISPR/Cas9 genome editing. Female and male Esr1-Q mice are infertile and have similar phenotypes to αERKO mice. Overall phenotypes of the Esr1-Q mice correspond to those observed in the patient with Q375H. Finally, we explore the effects of a synthetic progestogen and a gonadotropin-releasing hormone inhibitor in the Esr1-Q mice for potentially reversing the impaired female reproductive tract function. These findings provide an important basis for understanding the molecular mechanistic consequences associated with EIS.
    MeSH term(s) Animals ; Estrogen Receptor alpha/chemistry ; Estrogen Receptor alpha/genetics ; Estrogen Receptor alpha/metabolism ; Estrogens/metabolism ; Female ; Humans ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Dynamics Simulation ; Mutation, Missense ; Protein Conformation ; Transcriptome
    Chemical Substances ESR1 protein, human ; Esr1 protein, mouse ; Estrogen Receptor alpha ; Estrogens ; Ligands
    Language English
    Publishing date 2020-04-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/endocr/bqaa050
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A mutant form of ERα associated with estrogen insensitivity affects the coupling between ligand binding and coactivator recruitment.

    Li, Yin / Coons, Laurel A / Houtman, René / Carlson, Kathryn E / Martin, Teresa A / Mayne, Christopher G / Melchers, Diana / Jefferson, Tanner B / Ramsey, J Tyler / Katzenellenbogen, John A / Korach, Kenneth S

    Science signaling

    2020  Volume 13, Issue 650

    Abstract: A homozygous missense mutation in the gene encoding the estrogen receptor α (ERα) was previously identified in a female patient with estrogen insensitivity syndrome. We investigated the molecular features underlying the impaired transcriptional response ... ...

    Abstract A homozygous missense mutation in the gene encoding the estrogen receptor α (ERα) was previously identified in a female patient with estrogen insensitivity syndrome. We investigated the molecular features underlying the impaired transcriptional response of this mutant (ERα-Q375H) and four other missense mutations at this position designed to query alternative mechanisms. The identity of residue 375 greatly affected the sensitivity of the receptor to agonists without changing the ligand binding affinity. Instead, the mutations caused changes in the affinity of coactivator binding and alterations in the balance of coactivator and corepressor recruitment. Comparisons among the transcriptional regulatory responses of these six ERα genotypes to a set of ER agonists showed that both steric and electrostatic factors contributed to the functional deficits in gene regulatory activity of the mutant ERα proteins. ERα-coregulator peptide binding in vitro and RIME (rapid immunoprecipitation mass spectrometry of endogenous) analysis in cells showed that the degree of functional impairment paralleled changes in receptor-coregulator binding interactions. These findings uncover coupling between ligand binding and coregulator recruitment that affects the potency rather than the efficacy of the receptor response without substantially altering ligand binding affinity. This highlights a molecular mechanism for estrogen insensitivity syndrome involving mutations that perturb a bidirectional allosteric coupling between ligand binding and coregulator binding that determines receptor transcriptional output.
    MeSH term(s) Binding Sites/genetics ; Drug Resistance/genetics ; Estrogen Receptor alpha/chemistry ; Estrogen Receptor alpha/genetics ; Estrogen Receptor alpha/metabolism ; Estrogens/metabolism ; Estrogens/pharmacology ; Gene Expression Regulation ; HEK293 Cells ; Hep G2 Cells ; Humans ; Kinetics ; Ligands ; Molecular Dynamics Simulation ; Mutation, Missense ; Nuclear Receptor Coactivator 1/genetics ; Nuclear Receptor Coactivator 1/metabolism ; Nuclear Receptor Coactivator 3/genetics ; Nuclear Receptor Coactivator 3/metabolism ; Protein Binding ; Protein Domains
    Chemical Substances Estrogen Receptor alpha ; Estrogens ; Ligands ; Nuclear Receptor Coactivator 1 (EC 2.3.1.48) ; Nuclear Receptor Coactivator 3 (EC 2.3.1.48)
    Language English
    Publishing date 2020-09-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.aaw4653
    Database MEDical Literature Analysis and Retrieval System OnLINE

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