马萨诸塞州总医院Konrad Hochedlinger小组的一项最新研究报道了二价染色质指导造血过程中的谱系规范。相关论文于2025年6月17日发表在《细胞》杂志上。
小组发现，所有形式的H3K4甲基化的小鼠，主要是H3-赖氨酸-4-转蛋氨酸（H3K4M）突变，屈服于所有主要血细胞类型的严重损失。表达H3K4M的造血干细胞（HSC）和承诺祖细胞数量正常，表明H3K4甲基化对于HSC的维持和承诺是必不可少的，但对于祖细胞成熟是必不可少的。在机制上，研究团队揭示了H3K4甲基化在造血干细胞和祖细胞中富集二价（即H3K4/H3K27甲基化）染色质状态的分化相关基因上反对抑制性H3K27甲基化的沉积。事实上，在H3K4甲基化缺失的小鼠中，通过同时抑制H3K27甲基化，课题组人员挽救了急性死亡、造血功能衰竭和基因失调。他们的结果为哺乳动物组织稳态中两个关键染色质标记之间的相互作用提供了功能证据。
据悉，发育基因表达受组蛋白H3赖氨酸4 （H3K4）和组蛋白H3赖氨酸27 （H3K27）甲基化的动态相互作用调控，但这些表观遗传修饰的生理作用仍不完全清楚。
附：英文原文
Title: Bivalent chromatin instructs lineage specification during hematopoiesis
Author: Masaki Yagi, Gracia Bonilla, Michael S. Hoetker, Nikolaos Tsopoulidis, Joy E. Horng, Chuck Haggerty, Alexander Meissner, Ruslan I. Sadreyev, Hanno Hock, Konrad Hochedlinger
Issue&Volume: 2025-06-17
Abstract: Developmental gene expression is regulated by the dynamic interplay of histone H3 lysine 4 (H3K4) and histone H3 lysine 27 (H3K27) methylation, yet the physiological roles of these epigenetic modifications remain incompletely understood. Here, we show that mice depleted for all forms of H3K4 methylation, using a dominant histone H3-lysine-4-to-methionine (H3K4M) mutation, succumb to a severe loss of all major blood cell types. H3K4M-expressing hematopoietic stem cells (HSCs) and committed progenitors are present at normal numbers, indicating that H3K4 methylation is dispensable for HSC maintenance and commitment but essential for progenitor cell maturation. Mechanistically, we reveal that H3K4 methylation opposes the deposition of repressive H3K27 methylation at differentiation-associated genes enriched for a bivalent (i.e., H3K4/H3K27-methylated) chromatin state in HSCs and progenitors. Indeed, by concomitantly suppressing H3K27 methylation in H3K4-methylation-depleted mice, we rescue the acute lethality, hematopoietic failure, and gene dysregulation. Our results provide functional evidence for the interaction between two crucial chromatin marks in mammalian tissue homeostasis.
DOI: 10.1016/j.cell.2025.05.011
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00561-6