Epigenetic control of female puberty.
The timing of puberty is controlled by many genes. The elements coordinating this process have not, however, been identified. Here we show that an epigenetic mechanism of transcriptional repression times the initiation of female puberty in rats. We identify silencers of the Polycomb group (PcG) as principal contributors to this mechanism and show that PcG proteins repress Kiss1, a puberty-activating gene. Hypothalamic expression of two key PcG genes, Eed and Cbx7, decreased and methylation of their promoters increased before puberty. Inhibiting DNA methylation blocked both events and resulted in pubertal failure. The pubertal increase in Kiss1 expression was accompanied by EED loss from the Kiss1 promoter and enrichment of histone H3 modifications associated with gene activation. Preventing the eviction of EED from the Kiss1 promoter disrupted pulsatile gonadotropin-releasing hormone release, delayed puberty and compromised fecundity. Our results identify epigenetic silencing as a mechanism underlying the neuroendocrine control of female puberty.
Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA. lomniczi@ohsu.edu
Alejandro
A
Lomniczi
Alberto
A
Loche
Juan Manuel
JM
Castellano
Oline K
OK
Ronnekleiv
Martha
M
Bosch
Gabi
G
Kaidar
J Gabriel
JG
Knoll
Hollis
H
Wright
Gerd P
GP
Pfeifer
Sergio R
SR
Ojeda
D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004958:Estradiol / Q000097:blood; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007031:Hypothalamus / Q000502:physiology*; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012741:Sexual Maturation / Q000502:physiology*
D006657:Histones; D059648:Kisspeptins; D063146:Polycomb-Group Proteins; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol