Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain

Junko Tomikawa, Yoshihisa Uenoyama, Makiko Ozawa, Tatsuya Fukanuma, Kenji Takase, Teppei Goto, Hitomi Abe, Nahoko Ieda, Shiori Minabe, Chikaya Deura, Naoko Inoue, Makoto Sanbo, Koichi Tomita, Masumi Hirabayashi, Satoshi Tanaka, Takuya Imamura, Hiroaki Okamura, Kei Ichiro Maeda, Hiroko Tsukamura

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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), inwhich 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 upregulated 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 neuronspecific 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.

Original languageEnglish
Pages (from-to)E1294-E1301
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number20
DOIs
Publication statusPublished - May 15 2012

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Anterior Hypothalamus
Gene Expression Regulation
Epigenomics
Estrogens
Brain
Histones
Genetic Promoter Regions
Arcuate Nucleus of Hypothalamus
Intergenic DNA
Gonadotropins
Gonadotropin-Releasing Hormone
Estrogen Receptors
Genes
Chromatin
Kisspeptins
Ventral Thalamic Nuclei
Gene Expression
Acetylation
Transgenic Mice
Cell Line

All Science Journal Classification (ASJC) codes

  • General

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Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain. / Tomikawa, Junko; Uenoyama, Yoshihisa; Ozawa, Makiko; Fukanuma, Tatsuya; Takase, Kenji; Goto, Teppei; Abe, Hitomi; Ieda, Nahoko; Minabe, Shiori; Deura, Chikaya; Inoue, Naoko; Sanbo, Makoto; Tomita, Koichi; Hirabayashi, Masumi; Tanaka, Satoshi; Imamura, Takuya; Okamura, Hiroaki; Maeda, Kei Ichiro; Tsukamura, Hiroko.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 20, 15.05.2012, p. E1294-E1301.

Research output: Contribution to journalArticle

Tomikawa, J, Uenoyama, Y, Ozawa, M, Fukanuma, T, Takase, K, Goto, T, Abe, H, Ieda, N, Minabe, S, Deura, C, Inoue, N, Sanbo, M, Tomita, K, Hirabayashi, M, Tanaka, S, Imamura, T, Okamura, H, Maeda, KI & Tsukamura, H 2012, 'Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 20, pp. E1294-E1301. https://doi.org/10.1073/pnas.1114245109
Tomikawa, Junko ; Uenoyama, Yoshihisa ; Ozawa, Makiko ; Fukanuma, Tatsuya ; Takase, Kenji ; Goto, Teppei ; Abe, Hitomi ; Ieda, Nahoko ; Minabe, Shiori ; Deura, Chikaya ; Inoue, Naoko ; Sanbo, Makoto ; Tomita, Koichi ; Hirabayashi, Masumi ; Tanaka, Satoshi ; Imamura, Takuya ; Okamura, Hiroaki ; Maeda, Kei Ichiro ; Tsukamura, Hiroko. / Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 20. pp. E1294-E1301.
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AU - Takase, Kenji

AU - Goto, Teppei

AU - Abe, Hitomi

AU - Ieda, Nahoko

AU - Minabe, Shiori

AU - Deura, Chikaya

AU - Inoue, Naoko

AU - Sanbo, Makoto

AU - Tomita, Koichi

AU - Hirabayashi, Masumi

AU - Tanaka, Satoshi

AU - Imamura, Takuya

AU - Okamura, Hiroaki

AU - Maeda, Kei Ichiro

AU - Tsukamura, Hiroko

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