UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.
UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.
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DOI：
10.1038/s41588-018-0114-z
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发表时间：
2018-06
期刊：
影响因子：
30.8
通讯作者：
Huntly BJP
中科院分区：
文献类型：
--
作者：
Gozdecka M;Meduri E;Mazan M;Tzelepis K;Dudek M;Knights AJ;Pardo M;Yu L;Choudhary JS;Metzakopian E;Iyer V;Yun H;Park N;Varela I;Bautista R;Collord G;Dovey O;Garyfallos DA;De Braekeleer E;Kondo S;Cooper J;Göttgens B;Bullinger L;Northcott PA;Adams D;Vassiliou GS;Huntly BJP
H3 K27赖氨酸特异性脱甲基酶UTX（或KDM 6A）是多种癌症中功能丧失突变的靶向。在这里，我们证明，UTX抑制髓性白血病通过非催化功能，其催化活性的Y-染色体parkinges，UTY（或KDM 6C）共享的属性。与此一致，我们证明了在多种人类癌症中UTX和UTY的伴随丢失/突变。从机制上讲，全球基因组分析显示H3 K27 Me 3只有微小的变化，但H3 K27 Ac和染色质可及性的显著和双向改变; H3 K4 Me 1修饰的主要损失; ETS和GATA因子结合的改变;以及Utx损失后基因表达的改变。通过整合蛋白质组学和基因组学分析，我们将这些变化与UTX对ATP依赖性染色质重塑的调节、COMPASS复合物的协调以及ETS因子在AML演变过程中的先锋活性增强联系起来。总的来说，我们的研究结果揭示了UTX通过抑制致癌ETS和上调肿瘤抑制加塔程序来抑制急性髓性白血病的双重作用。
The H3K27 lysine-specific demethylase UTX (or KDM6A) is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (or KDM6C). In keeping with this, we demonstrate concomitant loss/mutation of UTX and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27Me3, but significant and bidirectional alterations in H3K27Ac and chromatin accessibility; a predominant loss of H3K4Me1 modifications; alterations in ETS and GATA-factor binding; and altered gene expression after Utx loss. By integrating proteomic and genomic analyses, we link these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex and enhanced pioneering activity of ETS factors during evolution to AML. Collectively, our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs.
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组蛋白去甲基酶UTX调节不变天然杀伤T细胞的谱系特异性表观遗传程序。
影响因子：
30.5
作者：
Beyaz S;Kim JH;Pinello L;Xifaras ME;Hu Y;Huang J;Kerenyi MA;Das PP;Barnitz RA;Herault A;Dogum R;Haining WN;Yilmaz ÖH;Passegue E;Yuan GC;Orkin SH;Winau F
通讯作者：
Winau F
DOI：
10.1093/bioinformatics/btr670
发表时间：
2012-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Boeva V;Popova T;Bleakley K;Chiche P;Cappo J;Schleiermacher G;Janoueix-Lerosey I;Delattre O;Barillot E
通讯作者：
Barillot E
影响因子：
30.8
作者：
Faber ZJ;Chen X;Gedman AL;Boggs K;Cheng J;Ma J;Radtke I;Chao JR;Walsh MP;Song G;Andersson AK;Dang J;Dong L;Liu Y;Huether R;Cai Z;Mulder H;Wu G;Edmonson M;Rusch M;Qu C;Li Y;Vadodaria B;Wang J;Hedlund E;Cao X;Yergeau D;Nakitandwe J;Pounds SB;Shurtleff S;Fulton RS;Fulton LL;Easton J;Parganas E;Pui CH;Rubnitz JE;Ding L;Mardis ER;Wilson RK;Gruber TA;Mullighan CG;Schlenk RF;Paschka P;Döhner K;Döhner H;Bullinger L;Zhang J;Klco JM;Downing JR
通讯作者：
Downing JR
影响因子：
2.3
作者：
Ciau-Uitz, Aldo;Wang, Lu;Liu, Feng
通讯作者：
Liu, Feng
影响因子：
64.5
作者：
Groeschel, Stefan;Sanders, Mathijs A.;Delwel, Ruud
通讯作者：
Delwel, Ruud