Epigenomic comparison of distinct pluripotent stem cell states reveals a new class of enhancers with roles throughout mammalian development (ChIP-seq). Mus musculus

Naïve mouse embryonic stem cells (mESCs) and primed epiblast stem cells (mEpiSCs) represent successive snapshots of pluripotency during embryogenesis. Using transcriptomic and epigenomic mapping, we show that a small fraction of transcripts are differentially expressed between mESCs and mEpiSCs and these genes show expected changes in chromatin at their promoters and enhancers. Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically. In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which we term seed enhancers. In mEpiSCs, the naïve-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control. Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers. We propose that seed enhancers ensure proper enhancer utilization and transcriptional fidelity as mammalian cells transition from naïve pluripotency to a somatic regulatory program. Overall design: ChIP sequencing of histone modifications in mouse epiblast stem cells

初始态小鼠胚胎干细胞（mouse embryonic stem cells, mESCs）与始发态上胚层干细胞（epiblast stem cells, mEpiSCs）分别代表胚胎发生过程中多能性状态的连续阶段性快照。本研究通过转录组学与表观基因组学图谱分析，证实mESCs与mEpiSCs之间仅存在少量差异表达的转录本，且此类差异基因的启动子与增强子区域的染色质状态均呈现预期内的改变。令人意外的是，两类细胞中表达水平无显著差异的基因，其顺式调控环路亦存在显著差异。在mESCs中，此类基因与占主导地位的近端增强子以及处于休眠状态的远端增强子相关联，本研究将这类远端增强子命名为种子增强子。而在mEpiSCs中，初始态主导的增强子消失，种子增强子则接管了主要的转录调控功能。种子增强子具有更高的序列保守性，且在下游体细胞组织中呈现优先激活状态，通常可进一步扩展为超级增强子。本研究提出，当哺乳动物细胞从初始态多能性向体细胞调控程序转变时，种子增强子可保障增强子的正确利用与转录保真度。实验整体设计：小鼠上胚层干细胞组蛋白修饰的染色质免疫共沉淀测序（ChIP sequencing）