CTCF mediates CD8+ effector differentiation through dynamic redistribution and genomic reorganization.
CTCF mediates CD8+ effector differentiation through dynamic redistribution and genomic reorganization.
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DOI：
10.1084/jem.20221288
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发表时间：
2023-04-03
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Xue、Peng和同事采用包括Hi-C在内的多组学方法来证明CTCF通过动态再分配、局部染色质可及性控制和高阶基因组重组来促进细胞毒性效应分化，同时将记忆前体相关基因封闭在隔离的邻域内以抑制其激活。效应CD8+ T细胞的分化是由稳定和动态表达的转录调控因子指导的。在这里，我们发现原生向效应分化伴随着动态CTCF再分布和广泛的染色质结构变化。在CD8+ T细胞活化后，CTCF获得了新的结合位点并锚定了新的染色质相互作用，这些变化与染色质可及性增加和细胞毒性程序基因Tbx21、Ifng和Klrg1的表达升高有关。CTCF在初始状态下也从其前结合位点被逐出，同时在效应细胞中染色质相互作用减少，如在记忆前体相关基因（包括Il7r、Sell和Tcf7）中观察到的那样。CTCF的基因消融确实降低了细胞毒性基因的表达，但矛盾的是提高了记忆前体基因的表达。对比Hi-C分析显示，关键的记忆前体基因位于由组成型CTCF结合划定的绝缘区域内，它们的诱导可能是由于CTCF依赖的绝缘被破坏。因此，CTCF通过整合局部染色质可及性控制和高阶基因组重组来促进细胞毒效应分化。
Xue, Peng, and colleagues employed multiomics approaches including Hi-C to demonstrate that CTCF promotes cytotoxic effector differentiation through dynamic redistribution, local chromatin accessibility control, and higher-order genomic reorganization, while enclosing memory precursor–associated genes within insulated neighborhoods to restrain their activation. Differentiation of effector CD8+ T cells is instructed by stably and dynamically expressed transcription regulators. Here we show that naive-to-effector differentiation was accompanied by dynamic CTCF redistribution and extensive chromatin architectural changes. Upon CD8+ T cell activation, CTCF acquired de novo binding sites and anchored novel chromatin interactions, and these changes were associated with increased chromatin accessibility and elevated expression of cytotoxic program genes including Tbx21, Ifng, and Klrg1. CTCF was also evicted from its ex-binding sites in naive state, with concomitantly reduced chromatin interactions in effector cells, as observed at memory precursor–associated genes including Il7r, Sell, and Tcf7. Genetic ablation of CTCF indeed diminished cytotoxic gene expression, but paradoxically elevated expression of memory precursor genes. Comparative Hi-C analysis revealed that key memory precursor genes were harbored within insulated neighborhoods demarcated by constitutive CTCF binding, and their induction was likely due to disrupted CTCF-dependent insulation. CTCF thus promotes cytotoxic effector differentiation by integrating local chromatin accessibility control and higher-order genomic reorganization.
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影响因子：
32.4
作者：
Hu G;Cui K;Fang D;Hirose S;Wang X;Wangsa D;Jin W;Ried T;Liu P;Zhu J;Rothenberg EV;Zhao K
通讯作者：
Zhao K
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
32.4
作者：
Herndler-Brandstetter D;Ishigame H;Shinnakasu R;Plajer V;Stecher C;Zhao J;Lietzenmayer M;Kroehling L;Takumi A;Kometani K;Inoue T;Kluger Y;Kaech SM;Kurosaki T;Okada T;Flavell RA
通讯作者：
Flavell RA
影响因子：
30.5
作者：
通讯作者：
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