Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger.
Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger.
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DOI：
10.1038/nature08036
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发表时间：
2009-06-11
期刊：
影响因子：
64.8
通讯作者：
Allis, C. David
中科院分区：
文献类型：
--
作者：
Wang, Gang G.;Song, Jikui;Wang, Zhanxin;Dormann, Holger L.;Casadio, Fabio;Li, Haitao;Luo, Jun-Li;Patel, Dinshaw J.;Allis, C. David
组蛋白H3 Lys 4甲基化（H3 K4 me）被认为是调节基因表达、表观遗传状态和细胞身份的关键组分。H3 K4 me的生物学意义通过保守模块来解释，包括识别不同H3 K4 me状态的植物同源结构域（PHD）指。PHD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。在这里，我们报告，融合H3 K4-三甲基化（H3 K4 me 3）-结合PHD指，如C-末端PHD指JARID 1A或PHF 23（JARID 1APHD 3，PHF 23 PHD），一个共同的融合伴侣核孔蛋白-98（NUP 98）在人类白血病中鉴定，产生有效的癌蛋白，阻止造血分化和诱导急性髓性白血病（AML）。在这些过程中，一个PHD指，特异性识别H3 K4 me 3/2标记是必不可少的白血病。PHD指突变废除H3 K4 me 3结合也废除白血病转化。NUP 98-PHD融合阻止了许多编码谱系特异性转录因子（Hox（s）、Gata 3、Meis 1、Eya 1、Pbx 1）的基因座上的H3 K4 me 3的分化相关去除，并加强了它们的活性基因转录。从机制上讲，NUP 98-PHD融合体充当“染色质边界因子”，主导多梳介导的基因沉默，以将发育关键基因座“锁定”为活性染色质状态（具有诱导的组蛋白乙酰化的H3 K4 me 3），这是一种定义白血病干细胞的状态。总的来说，我们的研究代表了第一份报告，其中PHD手指，“效应器”的特定组蛋白修饰的失调，扰乱了发育关键位点的表观遗传动力学，灾难性的细胞命运决策，甚至导致肿瘤发生在发展过程中。
Histone H3 Lys4 methylation (H3K4me) was proposed as a critical component in regulating the gene expression, epigenetic states, and cellular identities. The biological meaning of H3K4me is interpreted via conserved modules including plant homeodomain (PHD) fingers that recognize varied H3K4me states. The dysregulation of PHD finger has been implicated in a variety of human diseases including cancers and immune or neurological disorders. Here we report that fusing an H3K4-trimethylation (H3K4me3)-binding PHD finger, such as the C-terminal PHD finger of JARID1A or PHF23 (JARID1APHD3, PHF23PHD), to a common fusion partner nucleoporin-98 (NUP98) as identified in human leukemias, generated potent oncoproteins that arrested hematopoietic differentiation and induced acute myeloid leukemia (AML). In these processes, a PHD finger that specifically recognizes H3K4me3/2 marks was essential for leukemogenesis. Mutations in PHD fingers that abrogated H3K4me3-binding also abolished leukemic transformation. NUP98-PHD fusion prevented the differentiation-associated removal of H3K4me3 at many loci encoding lineage-specific transcription factors (Hox(s), Gata3, Meis1, Eya1, Pbx1), and enforced their active gene transcription. Mechanistically, NUP98-PHD fusions act as ‘chromatin boundary factors’, dominating over polycomb-mediated gene silencing to ‘lock’ developmentally crucial loci into an active chromatin state (H3K4me3 with induced histone acetylation), a state that defined leukemia stem cells. Collectively, our studies represent the first report wherein the deregulation of PHD finger, ‘effector’ of specific histone modification, perturbs the epigenetic dynamics on developmentally critical loci, catastrophizes cellular fate decision-making, and even causes oncogenesis during development.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
64.5
作者：
Lee, TI;Jenner, RG;Young, RA
通讯作者：
Young, RA
影响因子：
2.9
作者：
FARROW, NA;MUHANDIRAM, R;KAY, LE
通讯作者：
KAY, LE
影响因子：
56.9
作者：
Lee, Min Gyu;Villa, Raffaella;Shiekhattar, Ramin
通讯作者：
Shiekhattar, Ramin
影响因子：
2.7
作者：
DELAGLIO, F;GRZESIEK, S;BAX, A
通讯作者：
BAX, A