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洛克菲勒大學表觀遺傳學實驗室，Sloan-Kettering癌癥研究中心結構生物學實驗室，Scripps研究所癌癥生物研究實驗室的研究者在最近的一期Nature上發表了Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger文章。提出了癌癥機理新的學說。 據介紹，癌癥多由染色質錯誤識別所致。一種錯誤表達的蛋白與DNA螺旋結構上的蛋白錯誤的結合會啟動錯誤的基因表達，這將導致細胞不受系統檢測而錯誤地生長。 幾種不同形式的血癌如急性髓細胞樣白血病就是由于染色質錯誤交換或是染色質異位所致。這樣的錯誤會導致蛋白翻譯過程出錯，產生同源異構的蛋白產物，這些就是染色質識別錯誤或是基因表達調節錯誤的結果。然而，這些錯誤是如何導致癌癥產生的呢，這一直都是個謎。 斯坦福大學的癌癥生物學家Or Gozami表示，Nature新發布的這篇研究成可以說是解開這個謎的答案。它不僅僅有助解開急性髓性白血病之謎，還有助解開其他癌癥之謎。 洛克菲勒大學等處的研究人員認為，在組蛋白的甲基化修飾過程出現的錯誤可能就是導致癌癥發生的原因。如果出現同源異構的蛋白（錯誤表達）與甲基化酶結合將導致啟動錯誤的細胞周期，這些都可能導致癌癥的發生。 研究人員首次報告，PHD finger導致的錯誤組蛋白修飾過程是促使癌變發生的原因。 推薦原始出處： Nature advance online publication 10 May 2009 | doi:10.1038/nature08036 Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger Gang G. Wang1, Jikui Song2, Zhanxin Wang2, Holger L. Dormann1, Fabio Casadio1, Haitao Li2, Jun-Li Luo3, Dinshaw J. Patel2 & C. David Allis1 1 Laboratory of Chromatin Biology & Epigenetics, The Rockefeller University, New York, New York 10065, USA 2 Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA 3 Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA Histone H3 lysine 4 methylation (H3K4me) has been proposed as a critical component in regulating gene expression, epigenetic states, and cellular identities1. The biological meaning of H3K4me is interpreted by conserved modules including plant homeodomain (PHD) fingers that recognize varied H3K4me states1, 2. 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 leukaemias4, 5, 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 leukaemogenesis. 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, catastrophizes cellular fate decision-making, and even causes oncogenesis during mammalian development. (責任編輯：Doctor001) |
