双价基因的启动子被H3K4me3（注释在赖氨酸4上的组蛋白H3的三甲基化）和H3K27me3（注释在赖氨酸27上的组蛋白H3的三甲基化）同时标记，对于发育和肿瘤发生起着关键作用。组蛋白H3赖氨酸4的单甲基化(H3K4me1)通常与增强子相关，但也存在于启动子区域，呈现为活性的双峰态或被抑制的单峰态。在启动子区域中出现H3K4me1和双价标记的共存在发育调控中的作用尚不清楚。我们报道了在分化过程中，双价启动子会经历H3K27me3-H3K4me1的转化，H3K27me3的失去伴随着H3K4me1的双峰态模式丢失或单峰态模式富集。更重要的是，这种转变调控特异性的基因表达来协调发育。此外，我们发现敲除PRC2（Polycomb repressive complex 2）的核心组分Eed（Embryonic Ectoderm Development）或Suz12（Suppressor of Zeste 12）在小鼠胚胎干细胞中人工产生H3K27me3-H3K4me1转换，使得部分双价启动子上的中内胚层相关基因上调，而外胚层相关基因下调，从而解释了在视黄酸（RA）诱导时观察到的神经外胚层分化障碍。最后，我们发现赖氨酸特异性去甲基化酶1（LSD1）与PRC2相互作用，并且在mESCs中对H3K27me3-H3K4me1转变作出贡献。以上发现表明，H3K27me3-H3K4me1转换通过调节特异性蛋白质表达在分化过程中发挥着关键作用，而LSD1通过与PRC2相互作用可以调制双价启动子中的H3K4me1模式。©2023. 作者。

Bivalent genes, of which promoters are marked by both H3K4me3 (trimethylation of histone H3 on lysine 4) and H3K27me3 (trimethylation of histone H3 on lysine 27), play critical roles in development and tumorigenesis. Monomethylation on lysine 4 of histone H3 (H3K4me1) is commonly associated with enhancers, but H3K4me1 is also present at promoter regions as an active bimodal or a repressed unimodal pattern. Whether the co-occurrence of H3K4me1 and bivalent marks at promoters plays regulatory role in development is largely unknown.We report that in the process of lineage differentiation, bivalent promoters undergo H3K27me3-H3K4me1 transition, the loss of H3K27me3 accompanies by bimodal pattern loss or unimodal pattern enrichment of H3K4me1. More importantly, this transition regulates tissue-specific gene expression to orchestrate the development. Furthermore, knockout of Eed (Embryonic Ectoderm Development) or Suz12 (Suppressor of Zeste 12) in mESCs (mouse embryonic stem cells), the core components of Polycomb repressive complex 2 (PRC2) which catalyzes H3K27 trimethylation, generates an artificial H3K27me3-H3K4me1 transition at partial bivalent promoters, which leads to up-regulation of meso-endoderm related genes and down-regulation of ectoderm related genes, thus could explain the observed neural ectoderm differentiation failure upon retinoic acid (RA) induction. Finally, we find that lysine-specific demethylase 1 (LSD1) interacts with PRC2 and contributes to the H3K27me3-H3K4me1 transition in mESCs.These findings suggest that H3K27me3-H3K4me1 transition plays a key role in lineage differentiation by regulating the expression of tissue specific genes, and H3K4me1 pattern in bivalent promoters could be modulated by LSD1 via interacting with PRC2.© 2023. The Author(s).