Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions

TLDR

Polycomb group proteins form chromatin‑modifying complexes essential for embryonic development and stem cell renewal, yet are frequently deregulated in cancer. The study aims to map PcG target genes genome‑wide in human embryonic fibroblasts and to delineate two distinct regulatory mechanisms in neuronal differentiation. Using genome‑wide location analysis, functional loss‑of‑function of PRC2 (EZH2, EED, SUZ12) and PRC1 (BMI‑1) components, and a neuronal differentiation model, the authors identify 40 derepressed genes and characterize PcG displacement or persistence during activation or repression. PRC1, PRC2, and H3K27me3 co‑occupy over 1,000 silenced genes enriched for developmental and fate‑decision functions; derepressed genes include osteogenic, adipogenic, and chondrogenic markers, while during differentiation PcGs are displaced from activated genes but remain bound to repressed genes, supporting a preprogrammed memory role for PcGs.

Abstract

The Polycomb group (PcG) proteins form chromatin-modifying complexes that are essential for embryonic development and stem cell renewal and are commonly deregulated in cancer. Here, we identify their target genes using genome-wide location analysis in human embryonic fibroblasts. We find that Polycomb-Repressive Complex 1 (PRC1), PRC2, and tri-methylated histone H3K27 co-occupy >1000 silenced genes with a strong functional bias for embryonic development and cell fate decisions. We functionally identify 40 genes derepressed in human embryonic fibroblasts depleted of the PRC2 components (EZH2, EED, SUZ12) and the PRC1 component, BMI-1. Interestingly, several markers of osteogenesis, adipogenesis, and chrondrogenesis are among these genes, consistent with the mesenchymal origin of fibroblasts. Using a neuronal model of differentiation, we delineate two different mechanisms for regulating PcG target genes. For genes activated during differentiation, PcGs are displaced. However, for genes repressed during differentiation, we paradoxically find that they are already bound by the PcGs in nondifferentiated cells despite being actively transcribed. Our results are consistent with the hypothesis that PcGs are part of a preprogrammed memory system established during embryogenesis marking certain key genes for repressive signals during subsequent developmental and differentiation processes.