Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
Cell. 2009 Dec 24;139(7):1303-14. doi: 10.1016/j.cell.2009.12.003.
Trimethylation on histone H3 lysine 27 (H3K27me3) by Polycomb repressive complex 2 (PRC2) regulates the balance between self-renewal and differentiation of embryonic stem cells (ESCs). The mechanisms controlling the activity and recruitment of PRC2 are largely unknown. Here we demonstrate that the founding member of the Jumonji family, JMJ (JUMONJI or JARID2), is associated with PRC2, colocalizes with PRC2 and H3K27me3 on chromatin, and modulates PRC2 function. In vitro JMJ inhibits PRC2 methyltransferase activity, consistent with increased H3K27me3 marks at PRC2 targets in Jmj(-/-) ESCs. Paradoxically, JMJ is required for efficient binding of PRC2, indicating that the interplay of PRC2 and JMJ fine-tunes deposition of the H3K27me3 mark. During differentiation, activation of genes marked by H3K27me3 and lineage commitments are delayed in Jmj(-/-) ESCs. Our results demonstrate that dynamic regulation of Polycomb complex activity orchestrated by JMJ balances self-renewal and differentiation, highlighting the involvement of chromatin dynamics in cell-fate transitions.
组蛋白 H3 赖氨酸 27 三甲基化（H3K27me3）由多梳抑制复合物 2（PRC2）调节胚胎干细胞（ESC）的自我更新和分化之间的平衡。控制 PRC2 活性和募集的机制在很大程度上尚不清楚。在这里，我们证明了 Jumonji 家族的创始成员 JMJ（JUMONJI 或 JARID2）与 PRC2 相关，与 PRC2 和染色质上的 H3K27me3 共定位，并调节 PRC2 功能。体外 JMJ 抑制 PRC2 甲基转移酶活性，与 Jmj（-/-）ESC 中 PRC2 靶标处 H3K27me3 标记增加一致。矛盾的是，JMJ 是 PRC2 有效结合所必需的，表明 PRC2 和 JMJ 的相互作用可微调 H3K27me3 标记的沉积。在分化过程中，Jmj（-/-）ESC 中标记有 H3K27me3 的基因的激活和谱系承诺延迟。我们的结果表明，由 JMJ 协调的多梳复合物活性的动态调节平衡了自我更新和分化，突出了染色质动力学在细胞命运转变中的参与。
