Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013 Paris, France.
Directors' research, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Nucleic Acids Res. 2023 Mar 21;51(5):2177-2194. doi: 10.1093/nar/gkad029.
X chromosome inactivation (XCI) is an essential process, yet it initiates with remarkable diversity in various mammalian species. XIST, the main trigger of XCI, is controlled in the mouse by an interplay of lncRNA genes (LRGs), some of which evolved concomitantly to XIST and have orthologues across all placental mammals. Here, we addressed the functional conservation of human orthologues of two such LRGs, FTX and JPX. By combining analysis of single-cell RNA-seq data from early human embryogenesis with various functional assays in matched human and mouse pluripotent stem- or differentiated post-XCI cells, we demonstrate major functional differences for these orthologues between species, independently of primary sequence conservation. While the function of FTX is not conserved in humans, JPX stands as a major regulator of XIST expression in both species. However, we show that different entities of JPX control the production of XIST at various steps depending on the species. Altogether, our study highlights the functional versatility of LRGs across evolution, and reveals that functional conservation of orthologous LRGs may involve diversified mechanisms of action. These findings represent a striking example of how the evolvability of LRGs can provide adaptative flexibility to constrained gene regulatory networks.
X 染色体失活（XCI）是一个必要的过程，但它在各种哺乳动物物种中以显著的多样性启动。XIST 是 XCI 的主要触发因素，在小鼠中由长非编码 RNA 基因（LRGs）的相互作用控制，其中一些与 XIST 同时进化，并在所有胎盘哺乳动物中具有同源物。在这里，我们研究了两个这样的 LRG（FTX 和 JPX）的人类同源物的功能保守性。通过将早期人类胚胎发生的单细胞 RNA-seq 数据与各种功能测定相结合，在匹配的人类和小鼠多能干细胞或 XCI 后分化细胞中进行，我们证明了这些同源物在物种间存在主要的功能差异，而与初级序列保守性无关。虽然 FTX 在人类中没有保守功能，但 JPX 是两种物种中 XIST 表达的主要调节剂。然而，我们表明，不同的 JPX 实体根据物种在不同步骤控制 XIST 的产生。总之，我们的研究强调了 LRG 在进化过程中的功能多样性，并揭示了同源 LRG 的功能保守性可能涉及多样化的作用机制。这些发现代表了一个引人注目的例子，说明 LRG 的可进化性如何为受限制的基因调控网络提供适应性灵活性。
