Three rules for epigenetic inheritance of human Polycomb silencing

Abstract Heritable expression of developmental genes is mediated by autoregulating transcription factor networks (TFNs) and Polycomb repressive chromatin silencing complexes (PRCs). Whether the mammalian Polycomb pathway mediates DNA sequence-independent epigenetic memory at genes being activated by TFNs remains unknown. Here, we show that, in human cells, newly induced Polycomb silencing at initially active developmental genes can be inherited for many cell divisions. However, when Polycomb silencing is similarly induced near ubiquitously expressed housekeeping genes, it is not heritable. Inheritance requires the recognition of CG-rich DNA by a Polycomb accessory protein, MTF2/PCL2, the histone H3 lysine 27 trimethylation (H3K27me3) and histone H2A lysine 119 mono-ubiquitination (H2AK119ub1) activities of PRC1 and PRC2, and their associated positive feedback (read-write). In the absence of H3K27me3, H2AK119ub1 can mediate inheritance of silencing by a mechanism that requires the recognition of H2AK119ub1 by the variant Polycomb Repressive Complex 1. These findings indicate that inheritance of Polycomb silencing in human cells (1) depends on sequence features of developmental gene loci (2) requires PRC1 and H2AK119ub1, and (3) can be mediated by PRC1-H2AK119ub1 independently of H3K27me3.