Benayoun Bérénice A, Caburet Sandrine, Dipietromaria Aurélie, Bailly-Bechet Marc, Batista Frank, Fellous Marc, Vaiman Daniel, Veitia Reiner A
INSERM U567, Team 21, Département de Génétique et Développement, Institut Cochin 75014, Paris, France.
Hum Mol Genet. 2008 Oct 15;17(20):3118-27. doi: 10.1093/hmg/ddn209. Epub 2008 Jul 16.
The Forkhead transcription factor FOXL2 plays a crucial role in ovarian development and maintenance. In humans, its mutations lead to craniofacial abnormalities, isolated or associated with ovarian dysfunction. Using a combinatorial approach, we identified and characterized a FoxL2 response element (FLRE) and showed that it is highly specific and that it diverges from that of other Forkhead transcription factors. This specificity should prevent aberrant regulation of FOXL2 targets by other members of the family and should prevent ectopic activation of the ovarian differentiation program in testes. We provide evidence that the FLRE is used in naturally occurring promoters. We show that polyAlanine expansions of FOXL2, which are the most frequent pathogenic mutations, induce a length-dependent loss of response on different artificial promoter reporters depending on the number and sequence of the FLREs that they contain. Thus, we provide clear mechanistic evidence explaining how the architecture of promoters influences their sensitivity to decreased transcription factor availability. Furthermore, we speculate that the generally absent ovarian phenotype of patients carrying the most frequent polyAlanine expansion should come from its ability to properly regulate high-affinity ovarian targets. The existence of critical high-affinity ovarian targets would be compatible with the role of FOXL2 in reproduction and ensure developmental and functional robustness. Taken together, our results give mechanistic insights on the molecular pathogenesis of FOXL2 polyAlanine expansions.
叉头转录因子FOXL2在卵巢发育和维持中起着关键作用。在人类中，其突变会导致颅面异常，可单独出现或与卵巢功能障碍相关。通过组合方法，我们鉴定并表征了一个FoxL2反应元件（FLRE），并表明它具有高度特异性，且与其他叉头转录因子的反应元件不同。这种特异性应可防止该家族其他成员对FOXL2靶标的异常调控，并防止睾丸中卵巢分化程序的异位激活。我们提供证据表明FLRE存在于天然启动子中。我们发现，FOXL2的聚丙氨酸扩展是最常见的致病突变，根据其所含FLRE的数量和序列，会导致不同人工启动子报告基因上的反应呈长度依赖性丧失。因此，我们提供了明确的机制证据，解释了启动子结构如何影响其对转录因子可用性降低的敏感性。此外，我们推测，携带最常见聚丙氨酸扩展的患者普遍缺乏卵巢表型，应归因于其正确调控高亲和力卵巢靶标的能力。关键高亲和力卵巢靶标的存在与FOXL2在生殖中的作用相符，并确保发育和功能的稳健性。综上所述，我们的结果为FOXL2聚丙氨酸扩展的分子发病机制提供了机制性见解。
