TY - JOUR
T1 - The methylcytosine dioxygenase ten-eleven translocase-2 (tet2) Enables elevated GnRH Gene expression and maintenance of male reproductive function
AU - Kurian, Joseph R.
AU - Louis, Somaja
AU - Keen, Kim L.
AU - Wolfe, Andrew
AU - Terasawa, Ei
AU - Levine, Jon E.
N1 - Funding Information:
This work was supported by Public Health Service grants from the National Institutes of Health R00ES020878 (to J.R.K.), 2R01HD011355 (to E.T.), and 1R01HD068777 (to J.E.L.). This work was also supported by the National Science Foundation IOS Grant 1049849 "Research Coordination Network for Epigenetics, Behavior and Reproduction.".
Publisher Copyright:
© Copyright 2016 by the Endocrine Society.
PY - 2016/9
Y1 - 2016/9
N2 - Reproduction depends on the establishment and maintenance of elevated GnRH neurosecretion. The elevation of primateGnRHrelease is accompanied by epigenetic changes. Specifically, cytosine residues within the GnRH gene promoter are actively demethylated, whereas GnRH mRNA levels and peptide release rise. Whether active DNA demethylation has an impact on GnRH neuron development and consequently reproductive function remains unknown. In this study, we investigated whether ten-eleven translocation (tet) enzymes, which initiate the process of active DNA demethylation, influence neuronal function and reproduction. We found that tet2 expression increases withagein the developingmousepreoptic area-hypothalamusandis substantially higher in a mature (GT1-7) than an immature (GN11) GnRH cell line. GnRH mRNA levels and mean GnRH peptide release elevated after overexpression of tet2 in GN11 cells, whereas CRISPR/cas9-mediated knockdown of tet2 in GT1-7 cells led to a significant decline in GnRH expression. Manipulations of tet2 expression altered tet2 genome binding and histone 3 lysine 4 trimethylation abundance at the GnRH promoter. Mice with selective disruption of tet2 in GnRH neurons (GnRH-specific tet2 knockout mice) exhibitednosign of altered pubertal timing in either sex, although plasmaLHlevels were significantly lower, and fecundity was altered specifically in adult male GnRH-specific tet2 knockout animals, indicating that tet2 may participate in the maintenance GnRH neuronal function. Exposure to bisphenol A, an environmental contaminant that alters GnRH neuron activity, caused a shift in tet2 subcellular localization and a decrease in histone 3 lysine 4 trimethylation abundance at the GnRH promoter. Finally, evaluation of tet2 protein interactions in GT1-7 cells suggests that the influence of tet2 on neuronal function are not limited to nuclear mechanisms but could depend on mitochondrial function, and RNA metabolism. Together, these studies implicate tet2 in the maintenance of GnRH neuronal function and neuroendocrine control of male reproduction.
AB - Reproduction depends on the establishment and maintenance of elevated GnRH neurosecretion. The elevation of primateGnRHrelease is accompanied by epigenetic changes. Specifically, cytosine residues within the GnRH gene promoter are actively demethylated, whereas GnRH mRNA levels and peptide release rise. Whether active DNA demethylation has an impact on GnRH neuron development and consequently reproductive function remains unknown. In this study, we investigated whether ten-eleven translocation (tet) enzymes, which initiate the process of active DNA demethylation, influence neuronal function and reproduction. We found that tet2 expression increases withagein the developingmousepreoptic area-hypothalamusandis substantially higher in a mature (GT1-7) than an immature (GN11) GnRH cell line. GnRH mRNA levels and mean GnRH peptide release elevated after overexpression of tet2 in GN11 cells, whereas CRISPR/cas9-mediated knockdown of tet2 in GT1-7 cells led to a significant decline in GnRH expression. Manipulations of tet2 expression altered tet2 genome binding and histone 3 lysine 4 trimethylation abundance at the GnRH promoter. Mice with selective disruption of tet2 in GnRH neurons (GnRH-specific tet2 knockout mice) exhibitednosign of altered pubertal timing in either sex, although plasmaLHlevels were significantly lower, and fecundity was altered specifically in adult male GnRH-specific tet2 knockout animals, indicating that tet2 may participate in the maintenance GnRH neuronal function. Exposure to bisphenol A, an environmental contaminant that alters GnRH neuron activity, caused a shift in tet2 subcellular localization and a decrease in histone 3 lysine 4 trimethylation abundance at the GnRH promoter. Finally, evaluation of tet2 protein interactions in GT1-7 cells suggests that the influence of tet2 on neuronal function are not limited to nuclear mechanisms but could depend on mitochondrial function, and RNA metabolism. Together, these studies implicate tet2 in the maintenance of GnRH neuronal function and neuroendocrine control of male reproduction.
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U2 - 10.1210/en.2016-1087
DO - 10.1210/en.2016-1087
M3 - Article
C2 - 27384303
AN - SCOPUS:84985911954
SN - 0013-7227
VL - 157
SP - 3588
EP - 3603
JO - Endocrinology
JF - Endocrinology
IS - 9
ER -