In this study, Wang et al. describe the temporal kinetics of CTCF binding to embryonic chromatin preimplantation, showing that cleavage-specific CTCF binding occurs before zygotic genome activation, particularly at CTCF anchor sites and SINE B2 elements. During morula–blastocyst transition, the neuroprotective protein ADPN suppresses CTCF binding at these sites and drives transcriptional derepression of the transposable elements, thereby regulating cell differentiation and blastocyst development.