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Estrogen signaling, through estrogen receptor ?, regulates DNA methylation and its machinery in male germ line in adult rats.

ABSTRACT: Estrogen, through its receptors, regulates various aspects of spermatogenesis and male fertility. To understand the roles of estrogen receptors (ER? and ER?) in male fertility, we have developed in vivo selective ER agonist administration models. Treatment of adult male rats with ER? or ER? agonist for 60 d decreases fertility and litter size mainly due to increased pre- and post-implantation embryo loss. Since epigenetic mechanisms like DNA methylation play a crucial role in male fertility, we investigated the effects of the ER agonists on DNA methylation in spermatozoa. Treatment with ER? agonist causes a significant decrease in DNA methylation both at the global level and at the H19 differentially methylated region (DMR). This could be due to decrease in DNA methyltransferases in the testis upon ER? agonist treatment. The hypomethylation observed at the H19 DMR corroborates with aberrant expression of Igf2 and H19 imprinted genes in the resorbed embryos sired by ER? agonist-treated males. Thus, our study demonstrates that ER? regulates DNA methylation and methylating enzymes during adult rat spermatogenesis. Activation of estrogen signaling through ER? could therefore cause DNA methylation defects leading to impaired male fertility. These results define a role for estrogen in epigenetic regulation of male germ line, suggesting that epigenetic insults by exposure to environmental estrogens could potentially affect male fertility.

SUBMITTER: Dumasia K

PROVIDER: S-EPMC5501191 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Estrogen signaling, through estrogen receptor β, regulates DNA methylation and its machinery in male germ line in adult rats.

Dumasia Kushaan K Kumar Anita A Deshpande Sharvari S Balasinor Nafisa H NH

Epigenetics 20170331 6

Estrogen, through its receptors, regulates various aspects of spermatogenesis and male fertility. To understand the roles of estrogen receptors (ERα and ERβ) in male fertility, we have developed in vivo selective ER agonist administration models. Treatment of adult male rats with ERα or ERβ agonist for 60 d decreases fertility and litter size mainly due to increased pre- and post-implantation embryo loss. Since epigenetic mechanisms like DNA methylation play a crucial role in male fertility, we ...[more]

PMID: 28362134

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Project description:To avoid organ dysfunction as a consequence of tissue diminution or tumorous growth, a tight balance between cell proliferation and differentiation is maintained in metazoans. However, cell-intrinsic gene expression mechanisms controlling adult tissue homeostasis remain poorly understood. By focusing on the adult Caenorhabditis elegans reproductive tissue, we show that translational activation of mRNAs is a fundamental mechanism to maintain tissue homeostasis. Our genetic experiments identified the Trf4/5-type cytoplasmic poly(A) polymerase (cytoPAP) GLD-4 and its enzymatic activator GLS-1 to perform a dual role in regulating the size of the proliferative zone. Consistent with a ubiquitous expression of GLD-4 cytoPAP in proliferative germ cells, its genetic activity is required to maintain a robust proliferative adult germ cell pool, presumably by regulating many mRNA targets encoding proliferation-promoting factors. Based on translational reporters and endogenous protein expression analyses, we found that gld-4 activity promotes GLP-1/Notch receptor expression, an essential factor of continued germ cell proliferation. RNA-protein interaction assays documented also a physical association of the GLD-4/GLS-1 cytoPAP complex with glp-1 mRNA, and ribosomal fractionation studies established that GLD-4 cytoPAP activity facilitates translational efficiency of glp-1 mRNA. Moreover, we found that in proliferative cells the differentiation-promoting factor, GLD-2 cytoPAP, is translationally repressed by the stem cell factor and PUF-type RNA-binding protein, FBF. This suggests that cytoPAP-mediated translational activation of proliferation-promoting factors, paired with PUF-mediated translational repression of differentiation factors, forms a translational control circuit that expands the proliferative germ cell pool. Our additional genetic experiments uncovered that the GLD-4/GLS-1 cytoPAP complex promotes also differentiation, forming a redundant translational circuit with GLD-2 cytoPAP and the translational repressor GLD-1 to restrict proliferation. Together with previous findings, our combined data reveals two interconnected translational activation/repression circuitries of broadly conserved RNA regulators that maintain the balance between adult germ cell proliferation and differentiation.

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Estrogen signaling, through estrogen receptor ?, regulates DNA methylation and its machinery in male germ line in adult rats.

Publications

Estrogen signaling, through estrogen receptor β, regulates DNA methylation and its machinery in male germ line in adult rats.

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