Todd Christopher D, Ijaz Jannat, Torabi Fereshteh, Dovgusha Oleksandr, Bevan Stephen, Cracknell Olivia, Lohoff Tim, Clark Stephen, Argelaguet Ricard, Pierce Juliette, Kafetzopoulos Ioannis, Santambrogio Alice, Nichols Jennifer, von Meyenn Ferdinand, Günesdogan Ufuk, Schoenfelder Stefan, Reik Wolf
Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
Altos Labs, Cambridge Institute of Science, Granta Park, Cambridge, CB21 6GQ, UK.
Genome Biol. 2025 Jul 18;26(1):214. doi: 10.1186/s13059-025-03658-8.
Embryonic development requires the accurate spatiotemporal execution of cell lineage-specific gene expression programs, which are controlled by transcriptional enhancers. Developmental enhancers adopt a primed chromatin state prior to their activation. How this primed enhancer state is established and maintained and how it affects the regulation of developmental gene networks remains poorly understood.
Here, we use comparative multi-omic analyses of human and mouse early embryonic development to identify subsets of postgastrulation lineage-specific enhancers which are epigenetically primed ahead of their activation, marked by the histone modification H3K4me1 within the epiblast. We show that epigenetic priming occurs at lineage-specific enhancers for all three germ layers and that epigenetic priming of enhancers confers lineage-specific regulation of key developmental gene networks. Surprisingly in some cases, lineage-specific enhancers are epigenetically marked already in the zygote, weeks before their activation during lineage specification. Moreover, we outline a generalizable strategy to use naturally occurring human genetic variation to delineate important sequence determinants of primed enhancer function.
Our findings identify an evolutionarily conserved program of enhancer priming and begin to dissect the temporal dynamics and mechanisms of its establishment and maintenance during early mammalian development.
胚胎发育需要细胞谱系特异性基因表达程序在时空上精确执行，而这些程序由转录增强子控制。发育增强子在激活之前会呈现一种预激活的染色质状态。这种预激活的增强子状态是如何建立和维持的，以及它如何影响发育基因网络的调控，目前仍知之甚少。
在这里，我们通过对人类和小鼠早期胚胎发育进行比较多组学分析，以识别原肠胚形成后谱系特异性增强子的子集，这些增强子在激活之前就已在表观遗传上被预激活，以胚泡内的组蛋白修饰H3K4me1为标记。我们表明，表观遗传预激活发生在所有三个胚层的谱系特异性增强子上，并且增强子的表观遗传预激活赋予关键发育基因网络以谱系特异性调控。令人惊讶的是，在某些情况下，谱系特异性增强子在合子中就已经在表观遗传上被标记，比它们在谱系特化过程中激活的时间提前数周。此外，我们概述了一种可推广的策略，利用自然发生的人类遗传变异来描绘预激活增强子功能的重要序列决定因素。
我们的研究结果确定了一种进化上保守的增强子预激活程序，并开始剖析其在早期哺乳动物发育过程中建立和维持的时间动态及机制。
