European Institute of Oncology, IFOM-IEO Campus, Milan, Italy.
PLoS Genet. 2013;9(2):e1003292. doi: 10.1371/journal.pgen.1003292. Epub 2013 Feb 28.
Transcription factor (TF)-induced reprogramming of somatic cells into induced pluripotent stem cells (iPSC) is associated with genome-wide changes in chromatin modifications. Polycomb-mediated histone H3 lysine-27 trimethylation (H3K27me3) has been proposed as a defining mark that distinguishes the somatic from the iPSC epigenome. Here, we dissected the functional role of H3K27me3 in TF-induced reprogramming through the inactivation of the H3K27 methylase EZH2 at the onset of reprogramming. Our results demonstrate that surprisingly the establishment of functional iPSC proceeds despite global loss of H3K27me3. iPSC lacking EZH2 efficiently silenced the somatic transcriptome and differentiated into tissues derived from the three germ layers. Remarkably, the genome-wide analysis of H3K27me3 in Ezh2 mutant iPSC cells revealed the retention of this mark on a highly selected group of Polycomb targets enriched for developmental regulators controlling the expression of lineage specific genes. Erasure of H3K27me3 from these targets led to a striking impairment in TF-induced reprogramming. These results indicate that PRC2-mediated H3K27 trimethylation is required on a highly selective core of Polycomb targets whose repression enables TF-dependent cell reprogramming.
转录因子（TF）诱导体细胞重编程为诱导多能干细胞（iPSC）与染色质修饰的全基因组变化有关。多梳蛋白介导的组蛋白 H3 赖氨酸-27 三甲基化（H3K27me3）被认为是区分体细胞和 iPSC 表观基因组的标志性修饰。在这里，我们通过在重编程开始时使 H3K27 甲基转移酶 EZH2 失活，剖析了 H3K27me3 在 TF 诱导的重编程中的功能作用。我们的结果表明，令人惊讶的是，尽管 H3K27me3 全局缺失，但功能性 iPSC 的建立仍在继续。缺乏 EZH2 的 iPSC 有效地沉默了体细胞转录组，并分化为来自三个胚层的组织。值得注意的是，对 Ezh2 突变体 iPSC 细胞中 H3K27me3 的全基因组分析显示，该标记保留在一组高度选择的多梳靶标上，这些靶标富含发育调节剂，可控制谱系特异性基因的表达。从这些靶标中去除 H3K27me3 会导致 TF 诱导的重编程明显受损。这些结果表明，PRC2 介导的 H3K27 三甲基化在高度选择的多梳靶标的核心上是必需的，这些靶标的抑制使 TF 依赖性细胞重编程成为可能。
