Kisspeptin Induces Dynamic Chromatin Modifications to Control GnRH Gene Expression

H. J. Novaira, M. L. Sonko, Sally Radovick

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

In vitro studies have demonstrated an increase in GnRH gene expression associated with an elevated secretory response to kisspeptin administration, suggesting that kisspeptin mediates GnRH expression at both the secretory and pretranslational levels. However, the kisspeptin-mediated intracellular mechanisms associated with the dynamic chromatin modifications modulating GnRH gene expression are unclear. The studies in this manuscript describe specific histone modifications on the enhancer and promoter of the mouse GnRH (mGnRH) gene induced by kisspeptin in GnRH neuronal cell lines (GT1-7 cells). ChIP assays followed by quantitative real-time PCR (qPCR) demonstrate that 15 and 45 min of 10−9 M kisspeptin significantly increased histone 3 acetylation (H3Ac) at the kisspeptin response element (KsRE) contained between −3446 and −2806 bp of the mGnRH enhancer (GnRHen) in GT1-7 cells, while no changes were observed in the downstream neuron-specific element (NSE). Moreover, kisspeptin specifically induced acetylation of H3AcK14 and K27 and trimethylation of H3 lysine 4 at the KsRE (markers of active chromatin) and no changes in dimethylation of H3K9 (a marker associated with gene repression). Occupancy of RNA Pol II (RNAPII) and a differential carboxyl-terminal domain (CTD) phosphorylation pattern was observed. An interaction between the NSE and the KsRE via a chromatin loop in the mGnRH gene by kisspeptin was detected by the chromosome conformation capture assay (3C). In conclusion, these results demonstrate that kisspeptin induces histone acetylation/methylation and consequently enhances the formation of a chromatin loop in the mGnRH gene which results in known increase in kisspeptin-dependent mGnRH expression.

Original languageEnglish (US)
Pages (from-to)3315-3325
Number of pages11
JournalMolecular Neurobiology
Volume53
Issue number5
DOIs
StatePublished - Jul 1 2016

Fingerprint

Kisspeptins
Gonadotropin-Releasing Hormone
Chromatin
Gene Expression
Response Elements
Acetylation
Histones
Genes
Histone Code
Neurons
RNA Polymerase II
Methylation
Lysine

All Science Journal Classification (ASJC) codes

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Keywords

  • Chromatin conformation
  • GT1-7 cells
  • GnRH
  • Histone
  • Kisspeptin
  • OTX-2

Cite this

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abstract = "In vitro studies have demonstrated an increase in GnRH gene expression associated with an elevated secretory response to kisspeptin administration, suggesting that kisspeptin mediates GnRH expression at both the secretory and pretranslational levels. However, the kisspeptin-mediated intracellular mechanisms associated with the dynamic chromatin modifications modulating GnRH gene expression are unclear. The studies in this manuscript describe specific histone modifications on the enhancer and promoter of the mouse GnRH (mGnRH) gene induced by kisspeptin in GnRH neuronal cell lines (GT1-7 cells). ChIP assays followed by quantitative real-time PCR (qPCR) demonstrate that 15 and 45 min of 10−9 M kisspeptin significantly increased histone 3 acetylation (H3Ac) at the kisspeptin response element (KsRE) contained between −3446 and −2806 bp of the mGnRH enhancer (GnRHen) in GT1-7 cells, while no changes were observed in the downstream neuron-specific element (NSE). Moreover, kisspeptin specifically induced acetylation of H3AcK14 and K27 and trimethylation of H3 lysine 4 at the KsRE (markers of active chromatin) and no changes in dimethylation of H3K9 (a marker associated with gene repression). Occupancy of RNA Pol II (RNAPII) and a differential carboxyl-terminal domain (CTD) phosphorylation pattern was observed. An interaction between the NSE and the KsRE via a chromatin loop in the mGnRH gene by kisspeptin was detected by the chromosome conformation capture assay (3C). In conclusion, these results demonstrate that kisspeptin induces histone acetylation/methylation and consequently enhances the formation of a chromatin loop in the mGnRH gene which results in known increase in kisspeptin-dependent mGnRH expression.",
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Kisspeptin Induces Dynamic Chromatin Modifications to Control GnRH Gene Expression. / Novaira, H. J.; Sonko, M. L.; Radovick, Sally.

In: Molecular Neurobiology, Vol. 53, No. 5, 01.07.2016, p. 3315-3325.

Research output: Contribution to journalArticle

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