Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
Mol Cell. 2018 Apr 19;70(2):371-379.e5. doi: 10.1016/j.molcel.2018.02.027. Epub 2018 Mar 29.
The Polycomb repressor complex 2 (PRC2) is composed of the core subunits Ezh1/2, Suz12, and Eed, and it mediates all di- and tri-methylation of histone H3 at lysine 27 in higher eukaryotes. However, little is known about how the catalytic activity of PRC2 is regulated to demarcate H3K27me2 and H3K27me3 domains across the genome. To address this, we mapped the endogenous interactomes of Ezh2 and Suz12 in embryonic stem cells (ESCs), and we combined this with a functional screen for H3K27 methylation marks. We found that Nsd1-mediated H3K36me2 co-locates with H3K27me2, and its loss leads to genome-wide expansion of H3K27me3. These increases in H3K27me3 occurred at PRC2/PRC1 target genes and as de novo accumulation within what were previously broad H3K27me2 domains. Our data support a model in which Nsd1 is a key modulator of PRC2 function required for regulating the demarcation of genome-wide H3K27me2 and H3K27me3 domains in ESCs.
多梳抑制复合物 2 (PRC2) 由核心亚基 Ezh1/2、Suz12 和 Eed 组成，它介导了高等真核生物中组蛋白 H3 赖氨酸 27 上的所有二甲基化和三甲基化。然而，对于 PRC2 的催化活性如何被调控以在基因组范围内划分 H3K27me2 和 H3K27me3 区域，人们知之甚少。为了解决这个问题，我们在胚胎干细胞 (ESCs) 中绘制了 Ezh2 和 Suz12 的内源性互作组图谱，并将其与 H3K27 甲基化标记的功能筛选相结合。我们发现 Nsd1 介导的 H3K36me2 与 H3K27me2 共定位，其缺失导致 H3K27me3 在全基因组范围内扩张。这些 H3K27me3 的增加发生在 PRC2/PRC1 靶基因上，并且在先前广泛的 H3K27me2 区域内作为从头积累。我们的数据支持这样一种模型，即 Nsd1 是 PRC2 功能的关键调节剂，对于调节 ESCs 中全基因组 H3K27me2 和 H3K27me3 区域的划分是必需的。
