Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 23, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2024067118
Keywords
androgen responsiveness; sex differentiation external genitalia Sp1; histone modifications
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Funding
- Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University
- Japan Society for the Promotion of Science KAKENHI Grants [19K24051, 17H06432, 18H02474, 18K06837, 18K06938]
- Grants-in-Aid for Scientific Research [19K24051, 18K06938, 17H06432, 18K06837, 18H02474] Funding Source: KAKEN
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This study reveals that the genomic environment for male-biased genes is conserved and acquires androgen responsiveness in both sexes. Sp1 plays a key role in establishing transcriptional competency for male-biased genes in both sexes. Genetic manipulation of MafB disrupts male-type urethral differentiation.
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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