ZIC2 and ZIC3 promote SWI/SNF recruitment to safeguard progression towards human primed pluripotency [ChIP-seq]

The primed epiblast acts as a transitional stage between the relatively homogeneous naïve epiblast and the gastrulating embryo. Its formation entails coordinated changes in regulatory circuits driven by strict epigenetic mechanisms. Using a multi-omic approach in human embryonic stem cell models across the spectrum of peri-implantation development, we demonstrate that the transcription factors ZIC2 and ZIC3 have overlapping but essential roles in opening primed-specific enhancers. Together they are essential to facilitate progression to and maintain primed pluripotency. ZIC2/3 achieve their function by recruiting SWI/SNF to chromatin and loss of ZIC2/3 or degradation of SWI/SNF both prevent enhancer activation. Loss of ZIC2/3 results in transcriptome changes consistent with perturbed Polycomb activity and a shift towards the expression of genes linked to mesendoderm differentiation. Additionally, we find an intriguing dependency on the transcriptional machinery for sustained recruitment of ZIC2/3 over a subset of primed-hESC specific enhancers. Taken together, ZIC2 and ZIC3 regulate highly dynamic lineage-specific enhancers and collectively act as key regulators of human primed pluripotency. Overall design: Profiling of genome-wide chromatin occupancy dynamics of ZIC2 and ZIC3 in primed hPSCs, and the effect on BRG1 and H3K27me3 occupancy upon loss of ZIC2 and ZIC3 or upon gain of ZIC2 in primed hESCs and naïve hESCs respectively.