Regulation of Cellular Differentiation Group, Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Experimental Hematology, German Cancer Research Center (DKFZ), Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), INF 280, 69120 Heidelberg, Germany.
Semin Cancer Biol. 2018 Aug;51:89-100. doi: 10.1016/j.semcancer.2017.09.008. Epub 2017 Sep 28.
Epigenome regulation is a critical mechanism that governs cell identity, lineage specification and developmental cell fates. With the advent of low-input and single-cell technologies as well as sophisticated cell labeling techniques, our understanding of transcriptional and epigenetic regulation of hematopoiesis is currently undergoing dramatic changes. Increasingly, evidence suggests that the epigenome conformation acts as a critical decision-making mechanism that instructs self-renewal, differentiation and developmental fates of hematopoietic progenitor cells. When dysregulated, this leads to the evolution of disease states such as leukemia. Indeed, aberrations in DNA methylation, histone modifications and genome architecture are characteristic features of many hematopoietic neoplasms in which epigenetic enzymes are frequently mutated. Sequencing studies and characterization of the epigenetic landscape in lymphomas, leukemias and in aged healthy individuals with clonal hematopoiesis have been indispensible to identify epigenetic regulators that play a role in transformation or pre-disposition to hematopoietic malignancies. In this review, we outline the current view of the hematopoietic system and the epigenetic mechanisms regulating hematopoiesis under homeostatic conditions, with a particular focus on the role of DNA methylation in this process. We will also summarize the current knowledge on the mechanisms underlying dysregulated DNA methylation in hematologic malignancies and how this contributes to our understanding of the physiological functions of epigenetic regulators in hematopoiesis.
表观基因组调控是一种关键的机制，它控制着细胞的身份、谱系特化和发育中的细胞命运。随着低投入和单细胞技术以及复杂的细胞标记技术的出现，我们对造血的转录和表观遗传调控的理解正在发生巨大的变化。越来越多的证据表明，表观基因组构象起着关键的决策机制的作用，指导造血祖细胞的自我更新、分化和发育命运。当失调时，这会导致疾病状态的发生，如白血病。事实上，DNA 甲基化、组蛋白修饰和基因组结构的异常是许多造血肿瘤的特征，其中表观遗传酶经常发生突变。对淋巴瘤、白血病和具有克隆性造血的老年健康个体的表观基因组景观进行测序研究和特征分析，对于确定在转化或倾向于发生造血恶性肿瘤中起作用的表观遗传调节剂是不可或缺的。在这篇综述中，我们概述了造血系统的当前观点以及在稳态下调节造血的表观遗传机制，特别关注 DNA 甲基化在这个过程中的作用。我们还将总结血液恶性肿瘤中失调的 DNA 甲基化的机制以及这如何有助于我们理解表观遗传调节剂在造血中的生理功能。
