Cell Reprogramming Requires Silencing of a Core Subset of Polycomb Targets

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（Transcription factor, TF）介导的体细胞向诱导多能干细胞（induced pluripotent stem cells, iPSC）重编程的过程，伴随全基因组范围的染色质修饰改变。多梳蛋白介导的组蛋白H3赖氨酸27三甲基化（H3K27me3）曾被提出作为区分体细胞与iPSC表观基因组的标志性修饰。本研究通过在重编程起始阶段灭活H3K27甲基转移酶EZH2，解析了H3K27me3在TF介导的体细胞重编程中的功能作用。研究结果意外发现，即便全局丢失H3K27me3，功能性iPSC的形成仍可正常进行。缺失EZH2的iPSC可有效沉默体细胞转录组，并能分化为三胚层来源的各类组织。值得注意的是，对Ezh2突变iPSC细胞中H3K27me3的全基因组分析显示，该修饰仍保留在一组经过高度筛选的多梳蛋白靶标上，这些靶标富含调控谱系特异性基因表达的发育调控因子。若清除这些靶标上的H3K27me3，则会显著损害TF介导的体细胞重编程过程。上述结果表明，多梳抑制复合体2（Polycomb Repressive Complex 2, PRC2）介导的H3K27三甲基化，仅需在高度选择性的核心多梳靶标上发挥作用，通过抑制这些靶标的表达即可支持TF依赖的细胞重编程。