title: Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain.
abstract: This study aims to determine the epigenetic mechanism regulating Kiss1 gene expression in the anteroventral periventricular nucleus (AVPV) to understand the mechanism underlying estrogen-positive feedback action on gonadotropin-releasing hormone/gonadotropin surge. We investigated estrogen regulation of the epigenetic status of the mouse AVPV Kiss1 gene locus in comparison with the arcuate nucleus (ARC), in which Kiss1 expression is down-regulated by estrogen. Histone of AVPV Kiss1 promoter region was highly acetylated, and estrogen receptor α was highly recruited at the region by estrogen. In contrast, the histone of ARC Kiss1 promoter region was deacetylated by estrogen. Inhibition of histone deacetylation up-regulated in vitro Kiss1 expression in a hypothalamic non-Kiss1-expressing cell line. Gene conformation analysis indicated that estrogen induced formation of a chromatin loop between Kiss1 promoter and the 3' intergenic region, suggesting that the intergenic region serves to enhance estrogen-dependent Kiss1 expression in the AVPV. This notion was proved, because transgenic reporter mice with a complete Kiss1 locus sequence showed kisspeptin neuron-specific GFP expression in both the AVPV and ARC, but the deletion of the 3' region resulted in greatly reduced GFP expression only in the AVPV. Taken together, these results demonstrate that estrogen induces recruitment of estrogen receptor α and histone acetylation in the Kiss1 promoter region of the AVPV and consequently enhances chromatin loop formation of Kiss1 promoter and Kiss1 gene enhancer, resulting in an increase in AVPV-specific Kiss1 gene expression. These results indicate that epigenetic regulation of the Kiss1 gene is involved in estrogen-positive feedback to generate the gonadotropin-releasing hormone/gonadotropin surge.
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Tomikawa
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Uenoyama
authors.forename: Makiko
authors.initials: M
authors.lastname: Ozawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fukanuma
authors.forename: Kenji
authors.initials: K
authors.lastname: Takase
authors.forename: Teppei
authors.initials: T
authors.lastname: Goto
authors.forename: Hitomi
authors.initials: H
authors.lastname: Abe
authors.forename: Nahoko
authors.initials: N
authors.lastname: Ieda
authors.forename: Shiori
authors.initials: S
authors.lastname: Minabe
authors.forename: Chikaya
authors.initials: C
authors.lastname: Deura
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoue
authors.forename: Makoto
authors.initials: M
authors.lastname: Sanbo
authors.forename: Koichi
authors.initials: K
authors.lastname: Tomita
authors.forename: Masumi
authors.initials: M
authors.lastname: Hirabayashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Takuya
authors.initials: T
authors.lastname: Imamura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okamura
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Maeda
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsukamura
mesh_terms: D000107:Acetylation; D000818:Animals; D020643:Anterior Thalamic Nuclei / Q000378:metabolism*; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D001483:Base Sequence; D021901:DNA, Intergenic / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D004967:Estrogens / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006657:Histones / Q000378:metabolism; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA
chemical_list: D021901:DNA, Intergenic; D004967:Estrogens; D006657:Histones; C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D049452:Green Fluorescent Proteins; D007987:Gonadotropin-Releasing Hormone