Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, 641-8509 Wakayama, Japan.
Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, 641-8509 Wakayama, Japan;
Proc Natl Acad Sci U S A. 2021 Jun 8;118(23). doi: 10.1073/pnas.2024067118.
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 a key regulator of male-specific differentiation, and Sp1 regulatory 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.
睾丸雄激素是建立外生殖器性别差异的主要内分泌因素。发育过程中雄激素暴露的程度已知会决定外生殖器在女性到男性特异性表型谱上的命运。然而，雄激素调节性别分化的机制尚未明确。在这里，我们表明，表达雄性偏倚基因的基因组环境以获得雌雄两性的雄激素反应性是保守的。组蛋白 H3 在赖氨酸 27 乙酰化 (H3K27ac) 和 H3K4 单甲基化 (H3K4me1) 以雄激素非依赖性的方式富集在雄性偏倚基因的增强子上。特异性蛋白 1 (Sp1) 作为雄激素受体的协同转录因子，调节 H3K27ac 的富集，在雌雄两性中建立雄性偏倚基因的保守转录能力。对男性特异性分化的关键调控因子和 Sp1 调控增强子元件的遗传操作破坏了男性型尿道分化。总之，这些发现表明雌雄两性的雄激素反应性是保守的，为外生殖器发育过程中性别命运的调节机制提供了深入了解。
