GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency [ESC & EpiLC]

During early development, pluripotent cells of the epiblast show extensive rewiring of enhancers with little associated change in gene expression. The mechanisms underlying and purpose of this rewiring are largely unknown. Here we identified a transcription factor, GRHL2, that is both necessary and sufficient to activate latent enhancers during the transition from naïve embryonic stem cells (ESC) to primed epiblast cells (EpiC). GRHL2 is necessary to maintain expression of its targets in EpiCs. However, these genes are already expressed at equivalent levels in ESCs, suggesting these genes switch enhancer usage during the transition. Identification of alternative enhancers driving these genes in ESCs uncovered an enrichment for the ESC-specific KLF transcription factors. While many KLF targets remain expressed in EpiCs, GRHL2 only regulates a specific subset promoting an epithelial program. These data suggest a model where a large naïve-specific transcriptional network is partitioned into smaller networks to uncouple their regulation in EpiCs, providing more flexibility in gene regulation during lineage specification. Overall design: RNA-seq in wildtype embryonic stem cells (ESCs) and wildtype epiblast-like cells (EpiLCs)

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Chen AF, Liu AJ, Krishnakumar R, Freimer JW, DeVeale B, Blelloch R