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Skeletal and gene-regulatory functions of nuclear sex steroid hormone receptors

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Abstract

The wide variety of sex hormone actions underlie bone growth and health, and their actions mediate gene regulation by the cognate nuclear receptors. Nuclear androgen and estrogen receptors (AR, and ERα/ERβ) are hormone-dependent and DNA binding- transcription regulatory factors, and gene regulation by sex hormones often accompany with chromatin remodeling under aid of a number of co-regulators. As sex hormone biosynthesis is under highly regulated systemic and local regulations, the skeletal actions of sex hormones could be inferred from only the phenotypic abnormalities in skeleton in mouse genetic models deficient of nuclear receptors selectively in specific types of bone cells as well as at specific cell differentiation stages. Anabolic androgen actions and anti-bone resorptive estrogen actions are discussed here from the phenotypic abnormalities in such model mice. Though rapid gene regulation by sex hormones may not require chromatin reorganization, dynamic chromatin reconfiguration looks to facilitate profound and long-term hormonal actions. In this review, we focus the recent findings in gene regulation at a chromatin level, particularly of the function of enhancer RNAs transcribed from strong enhancers, and in the role of liquid–liquid phase separation state in transcription initiation through chromatin reconfiguration.

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Acknowledgements

We thank Ms Mai Hirata for her preparation of the manuscript and the past group members for their contribution to the research on sex hormone actions. We sincerely apologize the colleagues in the related fields for only refereeing the limited numbers of the reports due to the space limitation.

Funding

This research work was funded by Tokiwa foundation (grant no. 2021), the practical development projects by Fukushima prefecture (grant no. 2018–2020).

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Authors and Affiliations

  1. Graduate School of Life Science and Engineering, Iryo Sosei University, 5-5-1, Iino, Chuo-dai, Iwaki, Fukushima, 9708551, Japan

    Akira Hayakawa, Tomohiro Kurokawa, Yoshiaki Kanemoto, Takahiro Sawada, Jinichi Mori & Shigeaki Kato

  2. Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki, Fukushima, Japan

    Akira Hayakawa, Tomohiro Kurokawa, Yoshiaki Kanemoto, Takahiro Sawada, Jinichi Mori & Shigeaki Kato

  3. Department of Hematology, Jyoban Hospital, Tokiwa Foundation, Iwaki, Fukushima, Japan

    Jinichi Mori

  4. School of Medicine, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan

    Tomohiro Kurokawa, Jinichi Mori & Shigeaki Kato

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  1. Akira Hayakawa
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  2. Tomohiro Kurokawa
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  4. Takahiro Sawada
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Correspondence to Shigeaki Kato.

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Hayakawa, A., Kurokawa, T., Kanemoto, Y. et al. Skeletal and gene-regulatory functions of nuclear sex steroid hormone receptors. J Bone Miner Metab 40, 361–374 (2022). https://doi.org/10.1007/s00774-021-01306-2

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