FP39-5 Elevated methylcytosine dioxygenase (Tet) levels stimulate GnRH gene expression in immature neurons

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP39-Pituitary
Monday, June 17, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:05 AM
Room 133 (Moscone Center)

Poster Board MON-113
Joseph Kurian*1 and Ei Terasawa2
1University of Wisconsin, Madison, WI, 2Univ of Wisconsin, Madison, WI
We previously found that increased activity of gonadotropin releasing hormone (GnRH) neurons is accompanied by epigenetic changes. Specifically, during neuronal maturation, GnRH mRNA levels rise while cytosine residues within the GnRH gene promoter are actively demethylated. Whether that demethylation of the promoter leads to increased gene expression and mature function of the GnRH neuron remains unknown. We aimed to determine the mechanisms of GnRH neuronal maturation and the role of gonadal steroids and kisspeptins in this process. Using two GnRH neuronal cell lines with immature (GN11) and mature (GT1-7) neuronal characteristics, we have begun investigating the relationship between epigenetic differentiation and mature GnRH neuronal function. We have found that expression of the enzymes Tet1 and Tet2 are drastically lower in the GN11 compared to the GT1-7 cell line. These enzymes were recently found to oxidize methylated cytosine residues both in vivo and in vitro, and consequently appear to be partly responsible for active demethylation of DNA. We also found that overexpression of Tet1 or Tet2 in GN11 cells increased GnRH mRNA levels 4 to 7 fold, which was close to the level of expression in the mature GT1-7 cell line. Further, stimulation of GN11 cells with kisspeptin (10-8M and 10-9M) increased Tet1 and GnRH expression. Exposure of GN11 cells to 17β-estradiol (10-8M and 10-9M) decreased GnRH mRNA and altered the subcellular localization of Tet enzymes. These studies implicate Tet enzymes as mediators of epigenetic control over GnRH neuronal maturation and possibly direct responses to gonadal steroid exposure.

Nothing to Disclose: JK, ET

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH K99 020878P51OD011106 / P51RR000167