二价染色质指导造血过程中的谱系规范

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-06-17 DOI:10.1016/j.cell.2025.05.011

Masaki Yagi, Gracia Bonilla, Michael S. Hoetker, Nikolaos Tsopoulidis, Joy E. Horng, Chuck Haggerty, Alexander Meissner, Ruslan I. Sadreyev, Hanno Hock, Konrad Hochedlinger

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引用次数: 0

摘要

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。在这里，我们表明，使用显性组蛋白h3 -赖氨酸-4-转蛋氨酸（H3K4M）突变，所有形式的H3K4甲基化缺失的小鼠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，我们揭示了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，我们挽救了急性死亡、造血功能衰竭和基因失调。我们的研究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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Bivalent chromatin instructs lineage specification during hematopoiesis

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Bivalent chromatin instructs lineage specification during hematopoiesis

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.

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.