The Transcription Factor Runx3 Establishes Chromatin Accessibility of cis-Regulatory Landscapes that Drive Memory Cytotoxic T Lymphocyte Formation.
The Transcription Factor Runx3 Establishes Chromatin Accessibility of cis-Regulatory Landscapes that Drive Memory Cytotoxic T Lymphocyte Formation.
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DOI：
10.1016/j.immuni.2018.03.028
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发表时间：
2018-04-17
期刊：
影响因子：
32.4
通讯作者：
Pipkin ME
中科院分区：
文献类型：
--
作者：
Wang D;Diao H;Getzler AJ;Rogal W;Frederick MA;Milner J;Yu B;Crotty S;Goldrath AW;Pipkin ME
T细胞受体(TCR)刺激幼稚的CD8+T细胞启动顺式调节环境的重新编程，以指定效应和记忆细胞毒性T淋巴细胞(CTL)的分化。我们绘制了天真细胞在TCR刺激过程中高度可及染色质的区域，发现转录因子(TF)Runx3在第一次细胞分裂之前促进了对记忆CTL特异性顺式调控区的可及性，并且对记忆CTL分化是必不可少的。RUNX3对于获得高度富含IRF、bZIP和Prdm1样Tf基序的区域，上调Tf IRF4和Blimp1，以及激活早期效应器和记忆前体细胞的基本CTL属性是特别需要的。RUNX3通过阻止TfT-bet的高表达，减缓效应细胞的增殖，抑制终末CTL分化，确保新生CTL分化为记忆性CTL。在反复感染过程中，RUNX3过表达增强了记忆CTL分化。因此，Runx3调控TCR刺激过程中染色质的可及性，并执行记忆CTL发育程序。在感染期间，幼稚CD8+T细胞染色质的可及性被重新编程。Wang等人。研究表明，转录因子Runx3在刺激原始CD8+T细胞时编程染色质的可及性，从而建立早期转录电路，驱动新生细胞毒性T淋巴细胞(CTL)的分化，并抑制末端分化，以确保它们发展为长期记忆CTL。
T cell receptor (TCR) stimulation of naïve CD8+ T cells initiates reprogramming of cis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naïve cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 promoted accessibility to memory CTL-specific cis-regulatory regions prior to the first cell division, and was essential for memory CTL differentiation. Runx3 was specifically required for accessibility to regions highly enriched with IRF, bZIP and Prdm1-like TF motifs, upregulation of TFs Irf4 and Blimp1, and activation of fundamental CTL attributes in early effector and memory precursor cells. Runx3 ensured nascent CTLs differentiated into memory CTLs by preventing high expression of the TF T-bet, slowing effector cell proliferation, and repressing terminal CTL differentiation. Runx3 overexpression enhanced memory CTL differentiation during iterative infections. Thus, Runx3 governs chromatin accessibility during TCR stimulation and enforces the memory CTL developmental program. Chromatin accessibility in naïve CD8+ T cells is globally reprogrammed during infection. Wang et al. show that the transcription factor Runx3 programs chromatin accessibility during stimulation of naïve CD8+ T cells, which establishes early transcriptional circuits that drive differentiation of nascent cytotoxic T lymphocytes (CTLs), and also represses terminal differentiation, to ensure they develop into long-lived memory CTLs.
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DOI：
10.1084/jem.20150194
发表时间：
2015-11-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Omilusik KD;Best JA;Yu B;Goossens S;Weidemann A;Nguyen JV;Seuntjens E;Stryjewska A;Zweier C;Roychoudhuri R;Gattinoni L;Bird LM;Higashi Y;Kondoh H;Huylebroeck D;Haigh J;Goldrath AW
通讯作者：
Goldrath AW
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
64.5
作者：
Bhatt DM;Pandya-Jones A;Tong AJ;Barozzi I;Lissner MM;Natoli G;Black DL;Smale ST
通讯作者：
Smale ST
影响因子：
32.4
作者：
He B;Xing S;Chen C;Gao P;Teng L;Shan Q;Gullicksrud JA;Martin MD;Yu S;Harty JT;Badovinac VP;Tan K;Xue HH
通讯作者：
Xue HH
影响因子：
10.5
作者：
Iwafuchi-Doi M;Zaret KS
通讯作者：
Zaret KS