A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation.
A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation.
复制标题
粘连蛋白在 T 细胞受体重排和胸腺细胞分化中的作用。
DOI：
10.1038/nature10312
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发表时间：
2011-08-10
期刊：
影响因子：
64.8
通讯作者：
Merkenschlager, Matthias
中科院分区：
文献类型：
--
作者：
Seitan, Vlad C.;Hao, Bingtao;Tachibana-Konwalski, Kikue;Lavagnolli, Thais;Mira-Bontenbal, Hegias;Brown, Karen E.;Teng, Grace;Carroll, Tom;Terry, Anna;Horan, Katie;Marks, Hendrik;Adams, David J.;Schatz, David G.;Aragon, Luis;Fisher, Amanda G.;Krangel, Michael S.;Nasmyth, Kim;Merkenschlager, Matthias
黏连蛋白通过将姐妹染色单体从S期DNA复制的时间保持在一起直到有丝分裂而使复制后DNA修复和染色体分离成为可能。越来越多的证据表明，粘着蛋白也形成长距离的染色体顺式相互作用，并可能与CTCF、介体或组织特异性转录因子一起调节基因表达。人类粘着蛋白病，如科尔内利亚德兰格综合征，被认为是由受损的非典型粘着蛋白功能引起的，但在细胞分裂相关和细胞分裂无关的粘着功能之间的明确区别-如果蝇，，-尚未在脊椎动物系统中得到证实。为了解决这一问题，我们在小鼠胸腺细胞发育过程中停止循环并重新排列其T细胞受体（TCR）α位点（Tcra）时，删除了胸腺细胞中的粘附素位点Rad 21。Rad 21缺陷的胸腺细胞具有正常的寿命并保留了分化能力，尽管效率降低。Rad 21的缺失导致了Tcralocus的染色质结构缺陷，在Tcralocus中，粘附结合位点位于TEA启动子和Eα增强子的侧翼，并将Tcra与散布的Tcrdelements和邻近的管家基因区分开来。长距离启动子-增强子相互作用、Tcra转录、募集重组机制的H3 K4 me 3组蛋白修饰和Tcra重排都需要粘附素。提供预先重排的TCR转基因在很大程度上挽救了胸腺细胞的分化，这表明在基因组中成千上万的潜在靶基因中，缺陷性TCR重排限制了粘附素缺陷型胸腺细胞的分化。这些研究结果坚定地建立了细胞分裂独立的作用，凝聚素在Tcralocus重排，并提供了一个全面的帐户的机制，凝聚素使细胞分化在一个良好的特点哺乳动物系统。
Cohesin enables post-replicative DNA repair and chromosome segregation by holding sister chromatids together from the time of DNA replication in S phase until mitosis. There is growing evidence that cohesin also forms long-range chromosomalcis-interactions,,and may regulate gene expression,,,,,,,,in association with CTCF,, mediator or tissue-specific transcription factors. Human cohesinopathies such as Cornelia de Lange syndrome are thought to result from impaired non-canonical cohesin functions, but a clear distinction between the cell-division-related and cell-division-independent functions of cohesion—as exemplified inDrosophila,,—has not been demonstrated in vertebrate systems. To address this, here we deleted the cohesin locusRad21in mouse thymocytes at a time in development when these cells stop cycling and rearrange their T-cell receptor (TCR) α locus (Tcra).Rad21-deficient thymocytes had a normal lifespan and retained the ability to differentiate, albeit with reduced efficiency. Loss ofRad21led to defective chromatin architecture at theTcralocus, where cohesion-binding sites flank the TEA promoter and the Eα enhancer, and demarcateTcrafrom interspersedTcrdelements and neighbouring housekeeping genes. Cohesin was required for long-range promoter–enhancer interactions,Tcratranscription, H3K4me3 histone modifications that recruit the recombination machinery,andTcrarearrangement. Provision of pre-rearranged TCR transgenes largely rescued thymocyte differentiation, demonstrating that among thousands of potential target genes across the genome,,,, defectiveTcrarearrangement was limiting for the differentiation of cohesin-deficient thymocytes. These findings firmly establish a cell-division-independent role for cohesin inTcralocus rearrangement and provide a comprehensive account of the mechanisms by which cohesin enables cellular differentiation in a well-characterized mammalian system.
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影响因子：
30.5
作者：
Jackson, A;Kondilis, HD;Krangel, MS
通讯作者：
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影响因子：
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