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首页> 外文期刊>Nature >Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger
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Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger

机译：染色质结合型PHD手指失调引起的造血系统恶性肿瘤

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摘要

Histone H3 lysine 4 methylation (H3K4me) has been proposed as a critical component in regulating gene expression, epigenetic states, and cellular identities. The biological meaning of H3K4me is interpreted by conserved modules including plant homeodomain (PHD) fingers that recognize varied H3K4me states. The dysregulation of PHD fingers has been implicated in several human diseases, including cancers and immune or neurological disorders3. Here we report that fusing an H3K4-trimethylation (H3K4me3)-binding PHD finger, such as the carboxy-terminal PHD finger of PHF23 or JARID1A (also known as KDM5A or RBBP2), to a common fusion partner nucleoporin-98 (NUP98) as identified in human leukaemias, generated potent oncoproteins that arrested haematopoietic differentiation and induced acute myeloid leukaemia in murine models. In these processes, a PHD finger that specifically recognizes H3K4me3/2 marks was essential for leukae-mogenesis. Mutations in PHD fingers that abrogated H3K4me3 binding also abolished leukaemic transformation. NUP98-PHD fusion prevented the differentiation-associated removal of H3K4me3 at many loci encoding lineage-specific transcription factors (Hox(s), Gata3, Meis1, Eya1 and Pbx1), and enforced their active gene transcription in murine haematopoietic stem/progenitor cells. Mechanistically, NUP98-PHD fusions act as 'chromatin boundary factors', dominating over polycomb-mediated gene silencing to 'lock' developmentally critical loci into an active chromatin state (H3K4me3 with induced histone acetylation), a state that defined leukaemia stem cells. Collectively, our studies represent, to our knowledge, the first report that deregulation of the PHD finger, an 'effector' of specific histone modification, perturbs the epigenetic dynamics on developmentally critical loci, catastro-phizes cellular fate decision-making, and even causes oncogenesis during mammalian development.
机译：组蛋白H3赖氨酸4甲基化（H3K4me）已被提议作为调节基因表达，表观遗传状态和细胞身份的关键成分。 H3K4me的生物学意义由保守的模块解释，包括识别不同H3K4me状态的植物同源域（PHD）手指。 PHD手指的失调与多种人类疾病有关，包括癌症和免疫或神经系统疾病3。在这里我们报告说，将结合H3K4-三甲基化（H3K4me3）的PHD指状物（例如PHF23或JARID1A的羧基末端PHD指状物）（也称为KDM5A或RBBP2）融合为常见的融合伴侣nucleoporin-98（NUP98）在人类白血病中发现的这种蛋白会产生有效的癌蛋白，从而阻止造血分化并在小鼠模型中诱发急性髓细胞性白血病。在这些过程中，特异识别H3K4me3 / 2标记的PHD手指对于白细胞生成至关重要。 PHD手指中的突变消除了H3K4me3的结合，也消除了白血病的转化。 NUP98-PHD融合阻止了H3K4me3在编码谱系特异性转录因子（Hox（s），Gata3，Meis1，Eya1和Pbx1）的许多基因座处的分化相关去除，并在鼠类造血干/祖细胞中增强了它们的活性基因转录。从机制上讲，NUP98-PHD融合体起着“染色质边界因子”的作用，在多梳状介导的基因沉默中起着主导作用，从而将发育关键的基因座“锁定”到一个活跃的染色质状态（具有诱导的组蛋白乙酰化作用的H3K4me3），该状态定义了白血病干细胞。就我们所知，我们的研究代表了第一份报告，即PHD手指的放松调节，特定组蛋白修饰的“效应子”，扰乱了发育关键基因座的表观遗传动力学，严重破坏了细胞命运的决策，甚至导致哺乳动物发育过程中的致癌作用。

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  • 来源
    《Nature》 |2009年第7248期|847-851|共5页
  • 作者

    Gang G. Wang; Jikui Song; Zhanxin Wang; Holger L. Dormann; Fabio Casadio; Haitao Li; Jun-Li Luo; Dinshaw J. Patel; C. David Allis;

  • 作者单位

    Laboratory of Chromatin Biology & Epigenetics, The Rockefeller University, New York, New York 10065, USA;

    Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Laboratory of Chromatin Biology & Epigenetics, The Rockefeller University, New York, New York 10065, USA;

    Laboratory of Chromatin Biology & Epigenetics, The Rockefeller University, New York, New York 10065, USA;

    Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA;

    Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Laboratory of Chromatin Biology & Epigenetics, The Rockefeller University, New York, New York 10065, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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