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研究揭示转录因子Foxp3塑造调节性T细胞身份的机制
作者:小柯机器人 发布时间:2020/11/11 22:43:59

美国斯隆凯特林研究所Alexander Y. Rudensky、Joris van der Veeken等研究人员合作发现,转录因子Foxp3通过调整反式作用的中间因子来塑造调节性T细胞的身份。2020年11月10日,国际知名学术期刊《免疫》在线发表了这一成果。

通过利用野生来源的近交小鼠中自然发生的遗传变异(这能够鉴定驱动表观遗传特征的DNA序列基序),研究人员揭示了Foxp3的作用机制。在调节性T(Treg)细胞、常规CD4 T细胞和表达Foxp3报告基因无效等位基因的细胞静止和激活亚群中,染色质可及性、转录因子(TF)结合和基因表达模式揭示了大多数Foxp3依赖性变化发生在不受Foxp3结合的位点。
 
这些间接Foxp3靶标的染色质可及性取决于其他TF(包括TCF1)的DNA结合基序。Foxp3表达与TCF1减少和TCF1结合染色质区域的可及性降低相关。删除一个拷贝的Tcf7基因概括了染色质可及性的Foxp3依赖性负调控。因此,Foxp3通过微调其他主要染色质重塑TF(例如TCF1)的活性,在很大程度上间接地定义了Treg细胞的身份。
 
据介绍,Treg细胞的身份由谱系指定Foxp3定义。
 
附:英文原文

Title: The Transcription Factor Foxp3 Shapes Regulatory T Cell Identity by Tuning the Activity of trans-Acting Intermediaries

Author: Joris van der Veeken, Ariella Glasner, Yi Zhong, Wei Hu, Zhong-Min Wang, Regina Bou-Puerto, Louis-Marie Charbonnier, Talal A. Chatila, Christina S. Leslie, Alexander Y. Rudensky

Issue&Volume: 2020-11-10

Abstract: Regulatory T (Treg) cell identity is defined by the lineage-specifying transcriptionfactor (TF) Foxp3. Here we examined mechanisms of Foxp3 function by leveraging naturallyoccurring genetic variation in wild-derived inbred mice, which enables the identificationof DNA sequence motifs driving epigenetic features. Chromatin accessibility, TF binding,and gene expression patterns in resting and activated subsets of Treg cells, conventionalCD4 T cells, and cells expressing a Foxp3 reporter null allele revealed that the majority of Foxp3-dependent changes occurredat sites not bound by Foxp3. Chromatin accessibility of these indirect Foxp3 targetsdepended on the presence of DNA binding motifs for other TFs, including TCF1. Foxp3expression correlated with decreased TCF1 and reduced accessibility of TCF1-boundchromatin regions. Deleting one copy of the Tcf7 gene recapitulated Foxp3-dependent negative regulation of chromatin accessibility.Thus, Foxp3 defines Treg cell identity in a largely indirect manner by fine-tuningthe activity of other major chromatin remodeling TFs such as TCF1.

DOI: 10.1016/j.immuni.2020.10.010

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30451-9

期刊信息

Immunity:《免疫》,创刊于1994年。隶属于细胞出版社,最新IF:21.522
官方网址:https://www.cell.com/immunity/home
投稿链接:https://www.editorialmanager.com/immunity/default.aspx