研究揭示轉錄因子Foxp3塑造調節性T細胞身份的機制

研究揭示轉錄因子Foxp3塑造調節性T細胞身份的機制

作者：

小柯機器人

發布時間：2020/11/11 22:43:59

美國斯隆凱特林研究所Alexander Y. Rudensky、Joris van der Veeken等研究人員合作發現，轉錄因子Foxp3通過調整反式作用的中間因子來塑造調節性T細胞的身份。2020年11月10日，國際知名學術期刊《免疫》在線發表了這一成果。

通過利用野生來源的近交小鼠中自然發生的遺傳變異（這能夠鑑定驅動表觀遺傳特徵的DNA序列基序），研究人員揭示了Foxp3的作用機制。在調節性T（Treg）細胞、常規CD4 T細胞和表達Foxp3報告基因無效等位基因的細胞靜止和激活亞群中，染色質可及性、轉錄因子（TF）結合和基因表達模式揭示了大多數Foxp3依賴性變化發生在不受Foxp3結合的位點。

 

這些間接Foxp3靶標的染色質可及性取決於其他TF（包括TCF1）的DNA結合基序。Foxp3表達與TCF1減少和TCF1結合染色質區域的可及性降低相關。刪除一個拷貝的Tcf7基因概括了染色質可及性的Foxp3依賴性負調控。因此，Foxp3通過微調其他主要染色質重塑TF（例如TCF1）的活性，在很大程度上間接地定義了Treg細胞的身份。

 

據介紹，Treg細胞的身份由譜係指定Foxp3定義。

 

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