Scholarlink

<p>Mammalian sex determination is governed by two mutually antagonistic genetic programs that must be precisely balanced. Activation of <i>Sox9</i> initiates testis development, while its repression is essential for ovarian fate. The distal enhancer, Enh13, is essential for testicular <i>Sox9</i> expression, with its deletion or inactivation resulting in complete XY sex reversal. Here, we show that subtle mutations within Enh13, including a single-nucleotide insertion, produce the reciprocal phenotype: complete XX female-to-male sex reversal. Pro-female factors can strongly repress Enh13, suggesting they mediate <i>Sox9</i> silencing in ovaries. The small enhancer alterations facilitate inappropriate <i>Sox9</i> upregulation in the absence of <i>Sry</i>, triggering the testicular transcriptome and repressing ovarian gene expression. Mechanistically, these mutations disrupt the repressive effect of RUNX1, NR5A1 and GATA4, thereby reprogramming enhancer activity. Our findings identify Enh13 as a central regulatory hub, integrating opposing sex-specific cues, hence acting as a binary switch for gonadal fate.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

A single-nucleotide enhancer mutation overrides chromosomal sex to drive XX male development

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月9日

查看全文
  • Elisheva Abberbock,
  • Meshi Ridnik,
  • Isabelle Stévant,
  • Roni Weiss,
  • Carmel Bamberger,
  • Shelly Ziv Lhermann,
  • Maor Lubman,
  • Yumi Minyi Yao,
  • Ariel Afek,
  • Francis Poulat,
  • Nitzan Gonen

摘要

Mammalian sex determination is governed by two mutually antagonistic genetic programs that must be precisely balanced. Activation of Sox9 initiates testis development, while its repression is essential for ovarian fate. The distal enhancer, Enh13, is essential for testicular Sox9 expression, with its deletion or inactivation resulting in complete XY sex reversal. Here, we show that subtle mutations within Enh13, including a single-nucleotide insertion, produce the reciprocal phenotype: complete XX female-to-male sex reversal. Pro-female factors can strongly repress Enh13, suggesting they mediate Sox9 silencing in ovaries. The small enhancer alterations facilitate inappropriate Sox9 upregulation in the absence of Sry, triggering the testicular transcriptome and repressing ovarian gene expression. Mechanistically, these mutations disrupt the repressive effect of RUNX1, NR5A1 and GATA4, thereby reprogramming enhancer activity. Our findings identify Enh13 as a central regulatory hub, integrating opposing sex-specific cues, hence acting as a binary switch for gonadal fate.