洛克菲勒大學(xué)表觀遺傳學(xué)實(shí)驗(yàn)室,，Sloan-Kettering癌癥研究中心結(jié)構(gòu)生物學(xué)實(shí)驗(yàn)室,，Scripps研究所癌癥生物研究實(shí)驗(yàn)室的研究者在最近的一期Nature上發(fā)表了Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger文章。提出了癌癥機(jī)理新的學(xué)說,。
據(jù)介紹,，癌癥多由染色質(zhì)錯(cuò)誤識(shí)別所致,。一種錯(cuò)誤表達(dá)的蛋白與DNA螺旋結(jié)構(gòu)上的蛋白錯(cuò)誤的結(jié)合會(huì)啟動(dòng)錯(cuò)誤的基因表達(dá),，這將導(dǎo)致細(xì)胞不受系統(tǒng)檢測而錯(cuò)誤地生長,。
幾種不同形式的血癌如急性髓細(xì)胞樣白血病就是由于染色質(zhì)錯(cuò)誤交換或是染色質(zhì)異位所致。這樣的錯(cuò)誤會(huì)導(dǎo)致蛋白翻譯過程出錯(cuò),，產(chǎn)生同源異構(gòu)的蛋白產(chǎn)物,，這些就是染色質(zhì)識(shí)別錯(cuò)誤或是基因表達(dá)調(diào)節(jié)錯(cuò)誤的結(jié)果。然而,，這些錯(cuò)誤是如何導(dǎo)致癌癥產(chǎn)生的呢,，這一直都是個(gè)謎。
斯坦福大學(xué)的癌癥生物學(xué)家Or Gozami表示,，Nature新發(fā)布的這篇研究成可以說是解開這個(gè)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(xué)等處的研究人員認(rèn)為，在組蛋白的甲基化修飾過程出現(xiàn)的錯(cuò)誤可能就是導(dǎo)致癌癥發(fā)生的原因,。如果出現(xiàn)同源異構(gòu)的蛋白（錯(cuò)誤表達(dá)）與甲基化酶結(jié)合將導(dǎo)致啟動(dòng)錯(cuò)誤的細(xì)胞周期,，這些都可能導(dǎo)致癌癥的發(fā)生。
研究人員首次報(bào)告,，PHD finger導(dǎo)致的錯(cuò)誤組蛋白修飾過程是促使癌變發(fā)生的原因,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
