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The endocrine control of histone acetylation in regulating gonadotropin gene expression (HATs)
Start date: 01 Feb 2009, End date: 31 Jan 2013 PROJECT  FINISHED 

The gonadotropin hormones regulate reproduction, showing dynamic fluctuations in their expression levels across the life cycle to determine reproductive potential. The principle determinant of their expression is the hypothalamic hormone, GnRH, which stimulates both their synthesis and secretion. Aberrant GnRH exposure can stimulate precocious puberty, and we have shown previously that GnRH is able to overcome prolonged periods of gonadotropin gene repression, through removing histone deacetylases (HDACs) from their promoters. While HDACs repress transcription through nucleosome compaction, active histone acetylation on the protruding N-terminal tails of histones H3 and H4, both loosens the packaging of DNA and can serve as a signal for the binding of additional transcription factors. Research on the gonadotropins has revealed a number of transcription factors that activate both basal and GnRH-stimulated gene expression, but the role of the histone modifications has not been studied. The first aim of this study is to investigate which histone acetyl transferases (HATs) activate the gonadotropin gene promoters in response to GnRH treatment, whether they have any target specificity on the H3 and H4 tails, and how they are recruited. Histone acetylation is just one of the various covalent modifications which are required for activating transcription, although the regulation and interdependency of many of these modifications are not yet clear. We will therefore also study the requirement and consequence of the histone acetylation for other histone modifications such as phosphorylation and methylation at these gene loci. This is a novel aspect of GnRH signaling to the gonadotropin genes, that both provides a suitable model for understanding basic mechanisms of hormone-induced chromatin modifications, and also has implications for clinical relevance in the field of reproductive endocrinology.
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