Activation of Mouse Tcrb: Uncoupling RUNX1 Function from Its Cooperative Binding with ETS1.
Activation of Mouse Tcrb: Uncoupling RUNX1 Function from Its Cooperative Binding with ETS1.
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小鼠 Tcrb 的激活：将 RUNX1 功能与其与 ETS1 的协同结合解偶联。
DOI：
10.4049/jimmunol.1700146
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发表时间：
2017-08-01
期刊：
影响因子：
--
通讯作者：
Oltz EM
中科院分区：
文献类型：
--
作者：
Zhao JY;Osipovich O;Koues OI;Majumder K;Oltz EM
T细胞系定型需要多能祖细胞（MPP）中关键转录因子（TF）的协调，使其从其他谱系转变并巩固T细胞身份。MPP向T谱系转变的两个重要TF是RUNX 1和ETS 1，它们协同结合到整个基因组的复合位点，特别是参与T淋巴细胞生成的基因的调控元件中。定型胸腺细胞中T细胞受体β（Tcrb）位点的激活是这些细胞持续发育的关键过程，并且由具有两个RUNX-ETS复合位点的增强子Eβ介导。理解T细胞基因表达程序的一个突出问题是RUNX 1和ETS 1在增强子激活中是否具有独立的功能，可以从合作结合中分离出来。我们现在表明，RUNX 1是足够的激活内源性小鼠Eβ元件及其相邻的25 kb区域，通过独立拴系该TF没有巧合的ETS 1结合。此外，RUNX 1足以在整个Tcrb重组中心（RC）进行长距离启动子-E β环、核小体清除和稳健转录，跨越两个DβJβ簇。我们还发现，一个RUNX 1结构域，被称为负调控结构域的DNA结合（NRDB），可以补偿损失的ETS 1结合在相邻的网站。因此，我们已经定义了RUNX 1在T细胞发育增强子激活中的独立作用，以及其介导伴随RC启动子长距离诱导的染色质景观特异性变化的能力。
T lineage commitment requires the coordination of key transcription factors (TFs) in multi-potent progenitors (MPP) that transition them away from other lineages and cement T cell identity. Two important TFs for the MPP to T lineage transition are RUNX1 and ETS1, which bind cooperatively to composite sites throughout the genome, especially in regulatory elements for genes involved in T lymphopoiesis. Activation of the T cell receptor β (Tcrb) locus in committed thymocytes is a critical process for continued development of these cells, and is mediated by an enhancer, Eβ, which harbors two RUNX-ETS composite sites. An outstanding issue in understanding T cell gene expression programs is whether RUNX1 and ETS1 have independent functions in enhancer activation that can be dissected from cooperative binding. We now show that RUNX1 is sufficient to activate the endogenous mouse Eβ element and its neighboring 25 kb region by independently tethering this TF without coincidental ETS1 binding. Moreover, RUNX1 is sufficient for long-range promoter-Eβ looping, nucleosome clearance, and robust transcription throughout the Tcrb recombination center (RC), spanning both DβJβ clusters. We also find that a RUNX1 domain, termed the negative regulatory domain for DNA binding (NRDB), can compensate for the loss of ETS1 binding at adjacent sites. Thus, we have defined independent roles for RUNX1 in the activation of a T cell developmental enhancer, as well as its ability to mediate specific changes in chromatin landscapes that accompany long-range induction of RC promoters.
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影响因子：
5.2
作者：
David, R;Groebner, M;Franz, WM
通讯作者：
Franz, WM
DOI：
10.1084/jem.20141479
发表时间：
2015-01-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
Oltz EM
影响因子：
16
作者：
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通讯作者：
Talianidis, I
影响因子：
10.5
作者：
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通讯作者：
Grosschedl, R
DOI：
10.1084/jem.20101136
发表时间：
2010-12-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ji Y;Little AJ;Banerjee JK;Hao B;Oltz EM;Krangel MS;Schatz DG
通讯作者：
Schatz DG