MTF2 recruits Polycomb Repressive Complex 2 by helical shape-selective DNA binding

Polycomb repression of gene expression is essential for development, with a pivotal role played by trimethylation of histone H3 lysine 27 (H3K27me3) that is deposited by Polycomb Repressive Complex 2 (PRC2). The mechanism by which PRC2 is recruited to target genes has remained largely elusive, in particular in vertebrates. Here we demonstrate that MTF2, one of the three vertebrate homologs of Drosophila Polycomblike, is a DNA-binding, methylation-sensitive PRC2 recruiter in mouse embryonic stem cells. MTF2 directly binds to DNA and is essential for recruitment of PRC2 both in vitro and in vivo. Genome-wide recruitment of the PRC2 catalytic subunit EZH2 is abrogated in MTF2 knock-out cells, resulting in largely reduced H3K27me3 deposition. MTF2 selectively binds regions with a high density of unmethylated CpGs in a context of reduced helix twist, which distinguishes target from non-target CpG islands. These results demonstrate instructive recruitment of PRC2 to genomic targets by MTF2. ChIP-seq for Mtf2, Ezh2, H3K27me3, H3K4me3, Jarid2 and input for reference performed in WT, Mtf2, Jarid2 and Eed mutant mouse embryonic stem cells.