Garcia-Gomez Antonio, Li Tianlu, Kerick Martin, Català-Moll Francesc, Comet Natalia R, Rodríguez-Ubreva Javier, de la Rica Lorenzo, Branco Miguel R, Martín Javier, Ballestar Esteban
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Parque Tecnológico de La Salud (PTS), Granada, Spain.
Nucleic Acids Res. 2017 Sep 29;45(17):10002-10017. doi: 10.1093/nar/gkx666.
The plasticity of myeloid cells is illustrated by a diversity of functions including their role as effectors of innate immunity as macrophages (MACs) and bone remodelling as osteoclasts (OCs). TET2, a methylcytosine dioxygenase highly expressed in these cells and frequently mutated in myeloid leukemias, may be a key contributor to this plasticity. Through transcriptomic and epigenomic analyses, we investigated 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and gene expression changes in two divergent terminal myeloid differentiation processes, namely MAC and OC differentiation. MACs and OCs undergo highly similar 5hmC and 5mC changes, despite their wide differences in gene expression. Many TET2- and thymine-DNA glycosylase (TDG)-dependent 5mC and 5hmC changes directly activate the common terminal myeloid differentiation programme. However, the acquisition of differential features between MACs and OCs also depends on TET2/TDG. In fact, 5mC oxidation precedes differential histone modification changes between MACs and OCs. TET2 and TDG downregulation impairs the acquisition of such differential histone modification and expression patterns at MAC-/OC-specific genes. We prove that the histone H3K4 methyltransferase SETD1A is differentially recruited between MACs and OCs in a TET2-dependent manner. We demonstrate a novel role of these enzymes in the establishment of specific elements of identity and function in terminal myeloid differentiation.
髓系细胞的可塑性体现在多种功能上，包括作为巨噬细胞发挥固有免疫效应以及作为破骨细胞参与骨重塑。TET2是一种在这些细胞中高度表达且在髓系白血病中频繁发生突变的甲基胞嘧啶双加氧酶，可能是这种可塑性的关键促成因素。通过转录组学和表观基因组学分析，我们研究了在两个不同的终末髓系分化过程，即巨噬细胞分化和破骨细胞分化中，5-甲基胞嘧啶（5mC）、5-羟甲基胞嘧啶（5hmC）和基因表达的变化。尽管巨噬细胞和破骨细胞在基因表达上存在很大差异，但它们经历高度相似的5hmC和5mC变化。许多依赖TET2和胸腺嘧啶-DNA糖基化酶（TDG）的5mC和5hmC变化直接激活共同的终末髓系分化程序。然而，巨噬细胞和破骨细胞之间差异特征的获得也取决于TET2/TDG。事实上，5mC氧化先于巨噬细胞和破骨细胞之间差异组蛋白修饰的变化。TET2和TDG的下调会损害在巨噬细胞/破骨细胞特异性基因处获得这种差异组蛋白修饰和表达模式。我们证明组蛋白H3K4甲基转移酶SETD1A以TET2依赖的方式在巨噬细胞和破骨细胞之间被差异招募。我们展示了这些酶在终末髓系分化中建立特异性身份和功能元件方面的新作用。
