“It started out with a kiss. How did it end up like this? It was only a kiss, it was only a kiss” – The Killers clearly didn’t foresee the consequences of a meeting of lips; however, a new study into the links between nutrition and mammalian sexual development now suggests that a histone deacetylase-regulated “kiss” represent a crucial temporal mechanism regulating the onset of puberty.
Current worldwide trends of early onset of puberty, which brings with it a range of unwanted health deficits as an adult, have prompted research into what mechanisms control the onset of sexual development. While nutritional and metabolic signals play prominent regulatory roles and conditions associated with metabolic stress correlate with perturbed pubertal timing, we understand little of how nutritional and metabolic signals signal sexual development to begin.
These uncertainties led researchers led by Alejandro Lomniczi (Oregon Health and Science University, USA) and Manual Tena-Sempere (University of Cordoba, Spain) to the gonadotropin-releasing hormone (GnRH)-producing hypothalamic neurons of the arcuate nucleus that express the Kiss1 puberty-activating gene (and the kisspeptin protein product) in female rat brains. Fascinatingly, the team now reports that the Sirt1 histone deacetylase, which is regulated by nutritional energy levels, regulates Kiss1 gene expression in neurons to direct the onset of puberty.
Vazquez and Colleagues weighed-up all the data from their “osculatory” new study and came to the following conclusions:
- In arcuate nucleus hypothalamic neurons before puberty, Sirt1 interacts with a Polycomb silencing complex via Eed and generates a repressive chromatin environment at the Kiss1 promoter, thereby inhibiting Kiss1 expression, kisspeptin production, and GnRH release, and prohibiting early sexual development
- The normal decline in Sirt1 levels during development prompts the loss of Sirt1 binding at the Kiss1 promoter, leading to the creation of a more permissive chromatin environment, the expression of Kiss1, and the onset of sexual development
- While studying the importance of histone deacetylase activity, the authors discovered that the overexpression of Sirt1 in the rat hypothalamus leads to a reduced abundance of acetylated histones, lower Kiss1 expression, and delays in sexual development
- Finally, the team established that overweight rats (mimicking early-onset obesity) display decreased hypothalamic Sirt1 levels, leading to the early expression of Kiss1 (through the previously explained epigenetic mechanism), and the early onset of puberty
- However, underweight rats (mimicking under-nutrition) display elevated hypothalamic Sirt1 levels, leading to inhibition of Kiss1 expression, and the delay of sexual development
Overall, this exciting new study highlights Sirt1 as the link between nutritional status and the onset of puberty through the regulation of Kiss1 expression; a finding that may have clinical relevance -“Knowing how nutrition and specific molecules play a role in starting puberty early could one day help physicians prevent the condition in humans,” said Alejandro Lomniczi, one of the study’s corresponding authors.
So kiss those other papers goodbye, and learn more about the epigenetic regulation of puberty at Nature Communications, November 2018.