Department of Chemistry , Princeton University , Princeton , New Jersey 08544 , United States.
J Am Chem Soc. 2019 Sep 25;141(38):15029-15039. doi: 10.1021/jacs.9b02321. Epub 2019 Sep 17.
Polycomb Repressive Complex 2 (PRC2) catalyzes mono-, di-, and trimethylation of lysine 27 on histone H3 (H3K27me1-3) to control expression of genes important for differentiation and maintenance of cell identity. PRC2 activity is regulated by a number of different inputs, including allosteric activation by its product, H3K27me3. This positive feedback loop is thought to be important for the establishment of large domains of condensed heterochromatin. In addition to other chromatin modifications, ancillary subunits of PRC2, foremost JARID2, affect the rate of H3K27 methylation. Many gaps remain in our understanding of how PRC2 integrates these various signals to determine where and when to deposit H3K27 methyl marks. In this study, we utilize designer chromatin substrates to demonstrate that propagation of H3K27 methylation by the PRC2 core complex has geometrically defined preferences that are overridden by the presence of JARID2. Our studies also show that phosphorylation of JARID2 can partially regulate its ability to stimulate PRC2 activity. Collectively, these biochemical insights further our understanding of the mechanisms that govern PRC2 activity, and highlight a role for JARID2 in deposition of H3K27me3-containing repressive domains.
多梳抑制复合物 2（PRC2）催化组蛋白 H3 赖氨酸 27 的单、二和三甲基化（H3K27me1-3），以控制分化和维持细胞身份的重要基因的表达。PRC2 的活性受许多不同的输入调节，包括其产物 H3K27me3 的变构激活。这种正反馈回路被认为对于形成大的浓缩异染色质域很重要。除了其他染色质修饰外，PRC2 的辅助亚基，尤其是 JARID2，影响 H3K27 甲基化的速度。我们对 PRC2 如何整合这些各种信号以确定在何处以及何时沉积 H3K27 甲基标记的理解仍存在许多空白。在这项研究中，我们利用设计的染色质底物证明 PRC2 核心复合物传播 H3K27 甲基化具有几何定义的偏好，这些偏好被 JARID2 的存在所覆盖。我们的研究还表明，JARID2 的磷酸化可以部分调节其刺激 PRC2 活性的能力。总之，这些生化见解进一步加深了我们对调控 PRC2 活性的机制的理解，并强调了 JARID2 在 H3K27me3 富含抑制域沉积中的作用。
