Temporal degradation of PRC2 uncovers specific developmental dependencies

Abstract The repression of genes by Polycomb repressive complex 2 (PRC2) is well documented and constitutive deletion studies have highlighted its essential role in development. However, exactly how loss of the complex is linked to these phenotypes remains incompletely understood and difficult to study in vivo. Here, we applied a rapid protein degradation strategy combined with a scalable embryoid model to trigger temporal PRC2 loss. This allowed us to fine-map developmental failures and showed that in addition to the canonical posterior phenotypes, PRC2-depleted embryoids display unexpected ectopic expression of anterior and lateral lineage genes. We also find that while the baseline enrichment of H3K27me3 generally predicts lineage sensitivity, the presence of cognate transcription factors ultimately helps explain which genes respond to PRC2 loss. Our integrative expression and chromatin profiling highlights that in contrast to developmental genes, pluripotency-associated genes only fail to silence with early PRC2 depletion but are unaffected once cells exited pluripotency. Together, our results shed new light on the specific developmental requirements for PRC2-mediated repression at unprecedented temporal and lineage resolution.