Epigenetic control of the vasopressin promoter explains physiological ability to regulate vasopressin transcription in dehydration and salt loading states in the rat

Michael P Greenwood, Mingkwan Greenwood, Ben T Gillard, Su Yi Loh, Julian F R Paton, David Murphy

Research output: Contribution to journalArticle (Academic Journal)peer-review

5 Citations (Scopus)
256 Downloads (Pure)

Abstract

The synthesis of arginine vasopressin (Avp) in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus is sensitive to increased plasma osmolality and decreased blood volume, and, thus is robustly increased by both dehydration (increased plasma osmolality and decreased blood volume) and salt loading (increased plasma osmolality). Both stimuli result in functional remodelling of the SON and PVN, a process referred to as functional-related plasticity. Such plastic changes in the brain have recently been associated with altered patterns of DNA methylation at CpG residues, a process thought to be important for the regulation of gene transcription. In this regard, the proximal Avp promoter contains a number of CpG sites and is recognised as one of four CpG islands for the Avp gene, suggesting that methylation may be regulating Avp transcription. We show here that, in immortalised hypothalamic cell line 4B, the proximal Avp promoter is highly methylated, and treatment of these cells with DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine, to demethylate DNA, dramatically increases basal and stimulated Avp biosynthesis. We report here no changes in expression of DNA methyltransferases, Dnmt1 and Dnmt3a, but decreased expression of the demethylating enzyme ten-eleven-translocation 2, Tet2, in the SON by dehydration and salt loading. We found higher methylation of the SON Avp promoter in dehydrated but not salt loaded rats. By analysis of individual CpG sites, we observed hypomethylation, hypermethylation and no change in methylation of specific CpGs in the SON Avp promoter of the dehydrated rat. Using reporter gene assays, we show that mutation of individual CpGs can result in altered Avp promoter activity. We propose that methylation of the SON Avp promoter is necessary to co-ordinate the duel inputs of increased plasma osmolality and decreased blood volume on Avp transcription in the chronically dehydrated rat. This article is protected by copyright. All rights reserved.

Original languageEnglish
Number of pages11
JournalJournal of Neuroendocrinology
Volume28
Issue number4
Early online date1 Feb 2016
DOIs
Publication statusPublished - 25 Apr 2016

Keywords

  • methylation
  • arginine vasopressin
  • supraoptic nucleus
  • hyperosmotic
  • hypovolemia

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