During human development, a temporary organ is formed, the placenta, which invades the uterine wall to support nutrient, oxygen, and waste exchange between the mother and fetus until birth. Most of the human placenta is formed by a syncytial villous structure lined by syncytialized trophoblasts, a specialized cell type that forms via cell–cell fusion of underlying progenitor cells. Genetic and functional studies have characterized the membrane protein fusogens Syncytin-1 and Syncytin-2, both of which are necessary and sufficient for human trophoblast cell–cell fusion. However, identification and characterization of upstream transcriptional regulators regulating their expression have been limited. Here, using CRISPR knockout in an in vitro cellular model of syncytiotrophoblast development (BeWo cells), we found that the transcription factor TFEB, mainly known as a regulator of autophagy and lysosomal biogenesis, is required for cell–cell fusion of syncytiotrophoblasts. TFEB translocates to the nucleus, exhibits increased chromatin interactions, and directly binds the Syncytin-1 and Syncytin-2 promoters to control their expression during differentiation. Although TFEB appears to play a critical role in syncytiotrophoblast differentiation, ablation of TFEB largely does not affect lysosomal gene expression or lysosomal biogenesis in differentiating BeWo cells, suggesting a previously uncharacterized role for TFEB in controlling the expression of human syncytins.

中文翻译：

---

TFEB 在细胞与细胞融合过程中控制人合胞素的表达


在人类发育过程中，会形成一个临时器官，即胎盘，它会侵入子宫壁，以支持母亲和胎儿之间的营养、氧气和废物交换，直至出生。大部分人类胎盘是由合胞体绒毛结构形成，内衬合胞体滋养层，这是一种通过底层祖细胞的细胞-细胞融合形成的特殊细胞类型。遗传和功能研究已经确定了膜蛋白融合剂 Syncytin-1 和 Syncytin-2 的特征，两者对于人类滋养层细胞-细胞融合都是必要且充分的。然而，调节其表达的上游转录调节因子的鉴定和表征仍然有限。在这里，我们在合体滋养层发育的体外细胞模型（BeWo细胞）中使用CRISPR敲除，发现转录因子TFEB（主要作为自噬和溶酶体生物发生的调节剂）是合体滋养层细胞与细胞融合所必需的。 TFEB 易位到细胞核，表现出增强的染色质相互作用，并直接结合 Syncytin-1 和 Syncytin-2 启动子以在分化过程中控制它们的表达。尽管 TFEB 似乎在合体滋养层分化中发挥着关键作用，但 TFEB 的消除在很大程度上不会影响 BeWo 细胞分化中的溶酶体基因表达或溶酶体生物发生，这表明 TFEB 在控制人合胞素表达方面具有先前未表征的作用。