School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
RNA Biol. 2021 Sep;18(9):1354-1363. doi: 10.1080/15476286.2020.1850628. Epub 2020 Dec 9.
N-methyladenosine (mA) has emerged as a crucial epitranscriptomic mark which regulates a broad spectrum of physiological processes including stem cell differentiation. mA-binding YTHDF proteins have recently been proposed to mediate differentiation of leukemia cell in a redundant manner. However, whether these proteins play semblable roles in pluripotent stem cell remain largely unknown. Here, we showed the differential functions of YTHDF1 and YTHDF3 in controlling the differentiation of embryonic stem cells (ESCs). Depletion of YTHDF3 in ESCs resulted in loss of pluripotency with accelerated expressions of marker genes involved in formation of three germ layers. Phenotypic and transcriptomic analyses revealed that loss of YTHDF1 led to dramatic impairment of cardiomyocytes (CMs) differentiation, accompanied by downregulated CM-specific genes. While, knockdown of YTHDF3 accelerated differentiation through facilitating the expressions of CM-specific gene. Notably, YTHDF3 appears to modulate cellular differentiation partially through suppression of YTHDF1, supporting the distinguishable but interrelated roles of YTHDF1 and YTHDF3 in cell fate determination.
N6-甲基腺苷（m6A）已成为一种重要的转录后修饰标记，调节包括干细胞分化在内的广泛生理过程。最近提出，m6A 结合 YTHDF 蛋白以冗余方式介导白血病细胞的分化。然而，这些蛋白在多能干细胞中是否发挥类似的作用在很大程度上尚不清楚。在这里，我们展示了 YTHDF1 和 YTHDF3 在控制胚胎干细胞（ESC）分化中的差异功能。ESC 中 YTHDF3 的耗竭导致多能性丧失，与涉及三个胚层形成的标记基因的表达加速有关。表型和转录组分析表明，YTHDF1 的缺失导致心肌细胞（CM）分化的严重损伤，伴随着 CM 特异性基因的下调。然而，YTHDF3 通过促进 CM 特异性基因的表达加速分化。值得注意的是，YTHDF3 似乎部分通过抑制 YTHDF1 来调节细胞分化，支持 YTHDF1 和 YTHDF3 在细胞命运决定中具有可区分但相互关联的作用。
