ZIC2 and ZIC3 promote SWI/SNF recruitment to safeguard progression towards human primed pluripotency

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 transcription factors and epigenetic modifications. Using a multi-omic approach in human embryoni...

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Published inNature communications Vol. 15; no. 1; pp. 8539 - 16
Main Authors Hossain, Ishtiaque, Priam, Pierre, Reynoso, Sofia C., Sahni, Sahil, Zhang, Xiao X., Côté, Laurence, Doumat, Joelle, Chik, Candus, Fu, Tianxin, Lessard, Julie A., Pastor, William A.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 02.10.2024
Nature Publishing Group
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Summary: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 transcription factors and epigenetic modifications. 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 accomplish this by recruiting SWI/SNF to chromatin and loss of ZIC2/3 or degradation of SWI/SNF both prevent enhancer activation. Loss of ZIC2/3 also results in transcriptome changes consistent with perturbed Polycomb activity and a shift towards the expression of genes linked to differentiation towards the mesendoderm. 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. Here the authors identify ZIC2 and ZIC3 as key regulators of human primed pluripotency which recruit BRG1 to open primed hESC-specific enhancers.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-52431-1