Novel alternative splicing variants of Klf4 display different capacities for self-renewal and pluripotency in mouse embryonic stem cells

Embryonic stem (ES) cells are unique in their ability to self-renew indefinitely while maintaining pluripotency. Kruppel-like factor (Klf) 4 is an important member of the Klf family that is known to play a key role in pluripotency and somatic cell reprogramming. However, the identification and functional comparison of Klf4 splicing isoforms in mouse ESCs (mESCs) remains to be elucidated. Here, we identified three novel alternative splicing variants of Klf4 in mESCs-mKlf4-108, mKlf4-375 and mKlf4-1482-that are distinct from the previously known mKlf4-1449. mKlf4-1449 and mKlf4-1482 may stimulate the growth of ESCs, while mKlf4-108 can only promote the growth of ESCs in LIF(low)w/serum conditions. In addition, both mKlf4-1449 and mKlf4-1482 can inhibit the differentiation of mESCs. However, the ability of mKlf4-1482 to promote self-renewal and inhibit differentiation is not as strong as that of mKlf4-1449. In contrast, both mKlf4-108 and mKlf4-375 may have the ability to induce endodermal differentiation. Taken together, we have identified for the first time the existence of alternative splicing variants of mKlf4 and have revealed their different roles, which provide new insights into the contribution of Klf4 to the self-renewal and pluripotency of mouse ESCs. (C) 2020 Elsevier Inc. All rights reserved.

胚胎干细胞（ES细胞）具有独特的无限自我更新能力，同时保持多能性。克鲁佩尔样因子（Klf）4是Klf家族的一个重要成员，已知其在多能性和体细胞重编程中起关键作用。然而，小鼠胚胎干细胞（mES细胞）中Klf4剪接异构体的鉴定和功能比较仍有待阐明。在此，我们在mES细胞中鉴定出Klf4的三种新的可变剪接变体——mKlf4 - 108、mKlf4 - 375和mKlf4 - 1482，它们不同于先前已知的mKlf4 - 1449。mKlf4 - 1449和mKlf4 - 1482可能刺激胚胎干细胞的生长，而mKlf4 - 108只能在低白血病抑制因子（LIF）且有血清的条件下促进胚胎干细胞的生长。此外，mKlf4 - 1449和mKlf4 - 1482都能抑制mES细胞的分化。然而，mKlf4 - 1482促进自我更新和抑制分化的能力不如mKlf4 - 1449强。相反，mKlf4 - 108和mKlf4 - 375可能具有诱导内胚层分化的能力。综上所述，我们首次鉴定出mKlf4可变剪接变体的存在，并揭示了它们的不同作用，这为Klf4对小鼠胚胎干细胞自我更新和多能性的贡献提供了新的见解。（C）2020爱思唯尔公司。保留所有权利。