Sexual fate of murine external genitalia development: Conserved transcriptional competency for male-biased genes in both sexes
Sexual fate of murine external genitalia development: Conserved transcriptional competency for male-biased genes in both sexes
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DOI：
10.1073/pnas.2024067118
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发表时间：
2021-06-08
影响因子：
11.1
通讯作者：
Yamada, Gen
中科院分区：
文献类型：
--
作者：
Kajioka, Daiki;Suzuki, Kentaro;Yamada, Gen
睾丸雄激素是建立外生殖器性别差异的主要内分泌因素。众所周知，发育过程中雄激素暴露的程度决定了外生殖器在一系列女性到男性特定表型上的命运。然而，性别分化背后的雄激素调节机制尚不清楚。在这里，我们表明，男性偏向基因表达的基因组环境是保守的，以获得两性的雄激素反应性。组蛋白 H3 赖氨酸 27 乙酰化 (H3K27ac) 和 H3K4 单甲基化 (H3K4me1) 以不依赖雄激素的方式在偏雄性基因的增强子处富集。特异性蛋白 1 (Sp1) 作为雄激素受体的协同转录因子，调节 H3K27ac 富集，以建立两性中男性偏向基因的保守转录能力。 MafB（男性特异性分化的关键调节因子）和 Sp1 调节 MafB 增强子元件的基因操作会破坏男性型尿道分化。总而言之，这些发现证明了两性雄激素反应性的保守性，为外生殖器发育过程中性命运的调节机制提供了见解。
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.