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    GnRH Stimulates Peptidylarginine Deiminase Catalyzed Histone Citrullination in Gonadotrope Cells

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    Authors
    Khan, Shaihla A.
    Edwards, Brian S.
    Muth, Aaron
    Thompson, Paul R
    Cherrington, Brian D.
    Navratil, Amy M.
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2016-10-01
    Keywords
    Biochemistry
    Cellular and Molecular Physiology
    Endocrinology
    Enzymes and Coenzymes
    Medicinal-Pharmaceutical Chemistry
    Therapeutics
    
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    Link to Full Text
    https://doi.org/10.1210/me.2016-1085
    Abstract
    Peptidylarginine deiminase (PAD) enzymes convert histone tail arginine residues to citrulline resulting in chromatin decondensation. Our previous work found that PAD isoforms are expressed in female reproductive tissues in an estrous cycle-dependent fashion, but their role in the anterior pituitary gland is unknown. Thus, we investigated PAD expression and function in gonadotrope cells. The gonadotrope-derived LbetaT2 cell line strongly expresses PAD2 at the protein level compared with other PAD isoforms. Consistent with this, PAD2 protein expression is highest during the estrous phase of the estrous cycle and colocalizes with the LH beta-subunit in the mouse pituitary. Using the GnRH agonist buserelin (GnRHa), studies in LbetaT2 and mouse primary gonadotrope cells revealed that 30 minutes of stimulation caused distinct puncta of PAD2 to localize in the nucleus. Once in the nucleus, GnRHa stimulated PAD2 citrullinates histone H3 tail arginine residues at sites 2, 8, and 17 within 30 minutes; however, this effect and PAD2 nuclear localization was blunted by incubation of the cells with the pan-PAD inhibitor, biphenyl-benzimidazole-Cl-amidine. Given that PAD2 citrullinates histones in gonadotropes, we next analyzed the functional consequence of PAD2 inhibition on gene expression. Our results show that GnRHa stimulates an increase in LHbeta and FSHbeta mRNA and that this response is significantly reduced in the presence of the PAD inhibitor biphenyl-benzimidazole-Cl-amidine. Overall, our data suggest that GnRHa stimulates PAD2-catalyzed histone citrullination in gonadotropes to epigenetically regulate gonadotropin gene expression.
    Source
    Mol Endocrinol. 2016 Oct;30(10):1081-1091. Epub 2016 Sep 7. Link to article on publisher's site
    DOI
    10.1210/me.2016-1085
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/49992
    PubMed ID
    27603413
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1210/me.2016-1085
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