TY - JOUR
T1 - Sexual fate of murine external genitalia development
T2 - Conserved transcriptional competency for male-biased genes in both sexes
AU - Kajioka, Daiki
AU - Suzuki, Kentaro
AU - Matsushita, Shoko
AU - Hino, Shinjiro
AU - Sato, Tetsuya
AU - Takada, Shuji
AU - Isono, Kyoichi
AU - Takeo, Toru
AU - Kajimoto, Mizuki
AU - Nakagata, Naomi
AU - Nakao, Mitsuyoshi
AU - Suyama, Mikita
AU - DeFalco, Tony
AU - Miyagawa, Shinichi
AU - Yamada, Gen
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Drs. Sadaaki Maeda, Satoru Takahashi, Miho Terao, Takanori Hirano, Gerald Thiel, Yukiko Ogino, Takashi Baba, Yuichi Shima, Makoto Tachibana, Daisuke Matsumaru, Aki Murashima, Hiroko Suzuki, Kenji Toyota, Chikako Yokoyama, Mami Miyado, Yoshihiro Komatsu, Yu Hirano, Kei-ichi Katayama, Izumi Sasaki, Kenji Shimamura, Fan-Yan Wei, Shingo Usuki, Takashi Seki, Kei-ichiro Ishiguro, and Sho Morioka. We would like to express our appreciation to our laboratory colleagues and Benjamin Phillis. We also express our appreciation to Tomiko I. Iba and Yugi Rim for their valuable assistance. This work was supported by the Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University and Japan Society for the Promotion of Science KAKENHI Grants 19K24051, 17H06432, 18H02474, 18K06837, and 18K06938.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/6/8
Y1 - 2021/6/8
N2 - Testicular androgen is a master endocrine factor in the establishment of external genital sex differences. The degree of androgenic exposure during development is well known to determine the fate of external genitalia on a spectrum of female- to male-specific phenotypes. However, the mechanisms of androgenic regulation underlying sex differentiation are poorly defined. Here, we show that the genomic environment for the expression of male-biased genes is conserved to acquire androgen responsiveness in both sexes. Histone H3 at lysine 27 acetylation (H3K27ac) and H3K4 monomethylation (H3K4me1) are enriched at the enhancer of male-biased genes in an androgen-independent manner. Specificity protein 1 (Sp1), acting as a collaborative transcription factor of androgen receptor, regulates H3K27ac enrichment to establish conserved transcriptional competency for male-biased genes in both sexes. Genetic manipulation of MafB, a key regulator of male-specific differentiation, and Sp1 regulatory MafB enhancer elements disrupts male-type urethral differentiation. Altogether, these findings demonstrate conservation of androgen responsiveness in both sexes, providing insights into the regulatory mechanisms underlying sexual fate during external genitalia development.
AB - Testicular androgen is a master endocrine factor in the establishment of external genital sex differences. The degree of androgenic exposure during development is well known to determine the fate of external genitalia on a spectrum of female- to male-specific phenotypes. However, the mechanisms of androgenic regulation underlying sex differentiation are poorly defined. Here, we show that the genomic environment for the expression of male-biased genes is conserved to acquire androgen responsiveness in both sexes. Histone H3 at lysine 27 acetylation (H3K27ac) and H3K4 monomethylation (H3K4me1) are enriched at the enhancer of male-biased genes in an androgen-independent manner. Specificity protein 1 (Sp1), acting as a collaborative transcription factor of androgen receptor, regulates H3K27ac enrichment to establish conserved transcriptional competency for male-biased genes in both sexes. Genetic manipulation of MafB, a key regulator of male-specific differentiation, and Sp1 regulatory MafB enhancer elements disrupts male-type urethral differentiation. Altogether, these findings demonstrate conservation of androgen responsiveness in both sexes, providing insights into the regulatory mechanisms underlying sexual fate during external genitalia development.
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U2 - 10.1073/pnas.2024067118
DO - 10.1073/pnas.2024067118
M3 - Article
C2 - 34074765
AN - SCOPUS:85107373110
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 23
M1 - e2024067118
ER -