Fig. 8: Mechanistic model of ZNF263-mediated pluripotency priming in hESCs.

Schematic illustrating transcriptional regulation in wild-type (WT) and ZNF263-knockout (KO) hESCs. In WT hESCs, ZNF263 and its downstream target ZIC2 co-localize at the promoters and distal enhancers of bivalent genes, forming a positive feed-forward loop that drives the incipient expression of early differentiation genes. Simultaneously, ZNF263 and ZIC2 bind to the promoters of many pluripotency genes, hindering the regulatory effect of core pluripotency factors OCT4, SOX2, and NANOG (termed OSN) on these genes. This dual regulatory action of ZNF263 maintains a balanced primed pluripotency state in hESCs. Upon ZNF263 depletion, ZIC2 drastically loses its chromatin binding, and the feed-forward loop mediated by the ZNF263-ZIC2 axis collapses, leading to the transcriptional silencing of differentiation genes and rejuvenation of pluripotency gene expression in hESCs. ZNF263 plays a pivotal role in shaping the primed pluripotency transcriptional program, while its functional loss impairs the efficiency of pluripotency exit and subsequent lineage commitment in hESCs.