Tfcp2l1 represses multiple lineage commitment of mouse embryonic stem cells through MTA1 and LEF1

Tfcp2l1 is a transcription factor critical for mouse embryonic stem cell (mESC) self-renewal. How Tfcp2l1 maintains the pluripotent state of mESCs, however, remains unknown. Here, we show that knockdown of Tfcp2l1 in mESCs induces the expression of endoderm, mesoderm and trophectoderm markers. Functional analysis of mutant forms of Tfcp2l1 revealed that Tfcp2l1 depends on its N terminus and CP2-like domain to maintain the undifferentiated state of mESCs. The N terminus of Tfcp2l1 is mainly associated with the suppression of mesoderm and trophectoderm differentiation, while the CP2-like domain is closely related to the suppression of endoderm commitment. Further studies showed that MTA1 directly interacted with Tfcp2l1 protein and was indispensable for Tfcp2l1-mediated self-renewal-promoting effect and endoderm-inhibiting action. Tfcp2l1-mediated suppression of mesoderm and trophectoderm differentiation, however, is potentially through downregulation of Lef1 expression. Our study thus provides an expanded understanding of the function of Tfcp2l1 and the pluripotency regulation network of ESCs.