Department of Molecular Developmental Biology, Radboud University, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Department of Molecular Biology, Radboud University, Faculty of Science, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Nat Genet. 2018 Jul;50(7):1002-1010. doi: 10.1038/s41588-018-0134-8. Epub 2018 May 28.
Polycomb-mediated repression of gene expression is essential for development, with a pivotal role played by trimethylation of histone H3 lysine 27 (H3K27me3), which is deposited by Polycomb Repressive Complex 2 (PRC2). The mechanism by which PRC2 is recruited to target genes has remained largely elusive, particularly in vertebrates. Here we demonstrate that MTF2, one of the three vertebrate homologs of Drosophila melanogaster 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 knockout cells, resulting in greatly 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.
多梳蛋白介导的基因表达抑制对于发育至关重要，其中组蛋白 H3 赖氨酸 27 三甲基化（H3K27me3）起着关键作用，该修饰由多梳抑制复合物 2（PRC2）沉积。PRC2 被募集到靶基因的机制在很大程度上仍未被阐明，特别是在脊椎动物中。在这里，我们证明了果蝇 Polycomblike 的三个脊椎动物同源物之一 MTF2 是一种 DNA 结合、甲基化敏感的 PRC2 募集物，在小鼠胚胎干细胞中。MTF2 直接与 DNA 结合，对于 PRC2 的体外和体内募集都是必不可少的。在 Mtf2 敲除细胞中，PRC2 催化亚基 EZH2 的全基因组募集被阻断，导致 H3K27me3 沉积大大减少。MTF2 选择性地结合在低螺旋扭曲背景下具有高密度未甲基化 CpG 的区域，这将靶 CpG 岛与非靶 CpG 岛区分开来。这些结果表明 MTF2 对 PRC2 到基因组靶标的指导募集。
