Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling.
Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling.
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功能性转录因子靶网络阐明上皮重塑的控制。
DOI：
10.3390/cancers12102823
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发表时间：
2020-09-30
期刊：
影响因子：
5.2
通讯作者：
Essafi A
中科院分区：
文献类型：
--
作者：
Overton IM;Sims AH;Owen JA;Heale BSE;Ford MJ;Lubbock ALR;Pairo-Castineira E;Essafi A
细胞的身份是由基因表达，转录因子（TF）的顺式调控模块结合调节。解码TF结合模式和基因调控之间的关系是不平凡的，仍然是理解细胞决策的基本限制。我们开发了NetNC软件来预测TF靶点的功能性主动调节;在TF Snail、Twist和modENCODE高占用靶点（HOT）区域的9个数据集上进行了演示。Snail和Twist是上皮向间质转化（EMT）的典型驱动因素，EMT是一种在发育、肿瘤进展和纤维化中重要的细胞程序。预测的“中性”（非功能性）TF结合总是占来自统计学显著峰的候选靶基因的大多数（50%至95%），并且HOT区域具有比检查的大多数Snail和Twist数据集更高的功能性结合。我们的研究结果阐明了在发育和疾病中控制上皮可塑性的保守基因网络。我们确定了新的基因功能和网络模块，包括与notch信号传导和染色质组织调节的串扰，证明了上皮重塑过程中重塑Waddington表观遗传景观的网络。表达正交功能TF目标区分乳腺癌分子亚型和预测新的肿瘤生物学，与精确医学的影响。预测的入侵角色进行了验证，使用一个易处理的细胞模型，支持我们的方法。
Cell identity is governed by gene expression, regulated by transcription factor (TF) binding at cis-regulatory modules. Decoding the relationship between TF binding patterns and gene regulation is nontrivial, remaining a fundamental limitation in understanding cell decision-making. We developed the NetNC software to predict functionally active regulation of TF targets; demonstrated on nine datasets for the TFs Snail, Twist, and modENCODE Highly Occupied Target (HOT) regions. Snail and Twist are canonical drivers of epithelial to mesenchymal transition (EMT), a cell programme important in development, tumour progression and fibrosis. Predicted “neutral” (non-functional) TF binding always accounted for the majority (50% to 95%) of candidate target genes from statistically significant peaks and HOT regions had higher functional binding than most of the Snail and Twist datasets examined. Our results illuminated conserved gene networks that control epithelial plasticity in development and disease. We identified new gene functions and network modules including crosstalk with notch signalling and regulation of chromatin organisation, evidencing networks that reshape Waddington’s epigenetic landscape during epithelial remodelling. Expression of orthologous functional TF targets discriminated breast cancer molecular subtypes and predicted novel tumour biology, with implications for precision medicine. Predicted invasion roles were validated using a tractable cell model, supporting our approach.
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影响因子：
56.9
作者：
Acharya, U;Patel, S;Acharya, JK
通讯作者：
Acharya, JK
影响因子：
11.2
作者：
Cejalvo JM;Martínez de Dueñas E;Galván P;García-Recio S;Burgués Gasión O;Paré L;Antolín S;Martinello R;Blancas I;Adamo B;Guerrero-Zotano Á;Muñoz M;Nucíforo P;Vidal M;Pérez RM;Chacón López-Muniz JI;Caballero R;Peg V;Carrasco E;Rojo F;Perou CM;Cortés J;Adamo V;Albanell J;Gomis RR;Lluch A;Prat A
通讯作者：
Prat A
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
4.3
作者：
Chen J;Hu Z;Phatak M;Reichard J;Freudenberg JM;Sivaganesan S;Medvedovic M
通讯作者：
Medvedovic M
影响因子：
5.9
作者：
Chapellier, Marion;Bachelard-Cascales, Elodie;Schmidt, Xenia;Clement, Flora;Treilleux, Isabelle;Delay, Emmanuel;Jammot, Alexandre;Menetrier-Caux, Christine;Pochon, Gaetan;Besancon, Roger;Voeltzel, Thibault;de Fromentel, Claude Caron;Caux, Christophe;Blay, Jean-Yves;Iggo, Richard;Maguer-Satta, Veronique
通讯作者：
Maguer-Satta, Veronique