在从幼稚到启动多能性的过渡中，新兴人类发育增强剂的平衡和连接
Poising and connectivity of emergent human developmental enhancers in the transition from naive to primed pluripotency.
摘要(中文译文)
预备增强子（poised enhancers, PEs）由H3K4me1和Polycomb相关的H3K27me3共同标记，在类似于植入后上胚层的始发态（primed）人类多能干细胞（hPSCs）中常见，而在模拟植入前上胚层的幼稚态（naive）hPSCs中稀少。PEs与发育基因形成大量染色体接触，但其出现的时间、与增强子预备状态的关系及其功能意义仍不清楚。我们设计了高分辨率、靶向PE的Capture Hi-C，以绘制从幼稚态向始发态多能性转变过程中PE接触的图谱。我们发现增强子预备状态在该转变早期即出现，而接触则呈现多样的动态变化。在转变早期，PROTAC诱导的Polycomb抑制复合物2（PRC2）降解（而非抑制其H3K27甲基转移酶活性）会削弱PE连接性。最后，PE接触在发育激活或异位CRISPRa靶向之后仍然持续存在，并可介导长距离基因诱导。总之，这些发现揭示了PE连接性的时间与机制原理，并凸显了PE接触在建立发育基因表达模式中的潜在作用。
Abstract
Poised enhancers (PEs), co-marked by H3K4me1 and Polycomb-associated H3K27me3, are common in primed human pluripotent stem cells (hPSCs) resembling post-implantation epiblast but scarce in naive hPSCs modeling pre-implantation epiblast. PEs form abundant chromosomal contacts with developmental genes, but the timing of their emergence, their relationship to enhancer poising, and their functional significance remain unclear. We devised high-resolution, PE-targeted Capture Hi-C to map PE contacts during the transition from naive to primed pluripotency. We find that enhancer poising emerges early in the transition, while the contacts show diverse dynamics. PROTAC-induced degradation of Polycomb repressive complex 2 early in the transition, but not inhibition of its H3K27 methyltransferase activity, weakens PE connectivity. Finally, PE contacts persist after developmental activation or ectopic CRISPRa targeting and can mediate long-range gene induction. Together, these findings reveal the temporal and mechanistic principles of PE connectivity and highlight a potential role of PE contacts in establishing developmental gene expression patterns.
如何引用
AMA
Marina C Nocente, Monica Della Rosa, Andrew A Malcolm, George Lister, Isabella Savin, Helen Ray-Jones, et al. Poising and connectivity of emergent human developmental enhancers in the transition from naive to primed pluripotency.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117402.
APA
Marina C Nocente, Monica Della Rosa, Andrew A Malcolm, George Lister, Isabella Savin, Helen Ray-Jones, et al (2026). Poising and connectivity of emergent human developmental enhancers in the transition from naive to primed pluripotency.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117402
GB/T 7714
Marina C Nocente, Monica Della Rosa, Andrew A Malcolm, George Lister, Isabella Savin, Helen Ray-Jones, et al. Poising and connectivity of emergent human developmental enhancers in the transition from naive to primed pluripotency.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117402.
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