The LMO2 -25 Region Harbours GATA2-Dependent Myeloid Enhancer and RUNX-Dependent T-Lymphoid Repressor Activity.
The LMO2 -25 Region Harbours GATA2-Dependent Myeloid Enhancer and RUNX-Dependent T-Lymphoid Repressor Activity.
复制标题
DOI：
10.1371/journal.pone.0131577
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Calero-Nieto FJ
中科院分区：
文献类型：
--
作者：
Bonadies N;Göttgens B;Calero-Nieto FJ
Lim结构域2 （LMO2）是血管生成和造血细胞发育过程中所需的转录辅助因子。LMO2在除t细胞外的造血系统中广泛表达。在t细胞成熟过程中LMO2下调失败导致白血病，因此强调了LMO2表达的上下文依赖性调节的关键性质。我们之前发现了LMO2的远端调控元件（元件-25），它与近端启动子协同指导造血表达。在这里，我们剖析了元件-25的功能活性，并表明它由两个模块组成，具有独立的和细胞类型特异性的活性：一个3 ‘髓细胞增强子和一个5 ’ t细胞抑制子。髓系增强子在祖细胞中与GATA2结合，其活性依赖于一个高度保守的GATA基序，而t细胞抑制因子-25在t细胞中与核心结合因子结合，其抑制活性依赖于一个高度保守的RUNT基序。由于髓系增强子和附近的下游区域反复参与致癌易位，我们的数据表明-25增强子区域提供了一个易于易位的开放染色质环境，这反过来又由于邻近t细胞抑制因子的去除而导致t细胞中lmo2的异常表达。
Lim domain only 2 (LMO2) is a transcriptional co-factor required for angiogenesis and the specification of haematopoietic cells during development. LMO2 is widely expressed within haematopoiesis with the exception of T-cells. Failure to downregulate LMO2 during T-cell maturation leads to leukaemia, thus underlining the critical nature of context-dependent regulation of LMO2 expression. We previously identified a distal regulatory element of LMO2 (element -25) that cooperates with the proximal promoter in directing haematopoietic expression. Here we dissected the functional activity of element -25 and showed it to consist of two modules that conferred independent and cell-type specific activities: a 3’ myeloid enhancer and a 5’ T-cell repressor. The myeloid enhancer was bound by GATA2 in progenitors and its activity depended on a highly conserved GATA motif, whereas the T-cell repressor moiety of element -25 was bound by the Core Binding Factor in T-cells and its repressive activity depended on a highly conserved RUNT motif. Since the myeloid enhancer and nearby downstream region is recurrently involved in oncogenic translocations, our data suggest that the -25 enhancer region provides an open chromatin environment prone to translocations, which in turn cause aberrant LMO2expression in T-cells due to the removal of the adjacent T-cell repressor.
登录
查看更多内容
影响因子：
2.7
作者：
Hammond, SM;Crable, SC;Anderson, KP
通讯作者：
Anderson, KP
影响因子：
20.3
作者：
Beck, Dominik;Thoms, Julie A. I.;Pimanda, John E.
通讯作者：
Pimanda, John E.
DOI：
10.1073/pnas.88.10.4367
发表时间：
1991-05-01
影响因子：
11.1
作者：
BOEHM, T;FORONI, L;RABBITTS, TH
通讯作者：
RABBITTS, TH
影响因子：
20.3
作者：
Kundu, M;Compton, S;Liu, PP
通讯作者：
Liu, PP
影响因子：
20.3
作者：
Landry, JR;Kinston, S;Göttgens, B
通讯作者：
Göttgens, B