Nat. Genet. https://doi.org/10.1038/s41588-021-00964-2 (2021)
Non-genetic inheritance of gene expression states is thought to be essential for cells to maintain their specific identities. However, whether histone-modifying enzymes can control the epigenetic inheritance of local transcription states remains unknown. Polycomb proteins, in particular, are involved in the silencing of developmental genes, but have only been shown to mediate chromatin-based epigenetic memory in flies and plants. Writing in Nature Genetics, Raphaël Margueron and colleagues investigate whether transient inhibition of Polycomb repressive complex 2 (PRC2) in mouse neural progenitor cells results in changes in gene expression that are temporary or irreversible. The latter would suggest a disruption of the memory of the repressed state. The authors first find that temporary disruption of PRC2 leads to irreversible transcriptional changes, a property that is not observed in pluripotent stem cells but appears during cell differentiation. In addition, they show that although this memory state at PRC2 targets persists in cis, it does not rely solely on read-and-write propagation mechanisms of covalent histone modifications, which copy these marks during replication. PRC2-mediated epigenetic memory instead also depends on the context-specific activating inputs that oppose Polycomb proteins. The authors present computational simulations to support their model that transcriptional memory results from a double-negative feedback between PRC2-mediated silencing and active transcription. In conclusion, this study not only provides evidence of Polycomb-mediated epigenetic memory in mammals, but also shows that this process is finely regulated by additional transcriptional regulatory mechanisms that underlie cellular identity.
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