Overton Ian M, Sims Andrew H, Owen Jeremy A, Heale Bret S E, Ford Matthew J, Lubbock Alexander L R, Pairo-Castineira Erola, Essafi Abdelkader
MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Department of Systems Biology, Harvard University, Boston, MA 02115, USA.
Cancers (Basel). 2020 Sep 30;12(10):2823. doi: 10.3390/cancers12102823.
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 role were validated using a tractable cell model, supporting our approach.
细胞身份由基因表达决定，基因表达受转录因子（TF）与顺式调控模块结合的调控。解读TF结合模式与基因调控之间的关系并非易事，仍是理解细胞决策的一个基本限制。我们开发了NetNC软件来预测TF靶标的功能活性调控；并在九个数据集上对TF蜗牛、Twist和模式生物编码高占据靶标（HOT）区域进行了验证。蜗牛和Twist是上皮-间质转化（EMT）的典型驱动因子，EMT是一种在发育、肿瘤进展和纤维化中起重要作用的细胞程序。预测的“中性”（无功能）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区域的功能结合比大多数所检测的蜗牛和Twist数据集更高。我们的结果揭示了在发育和疾病中控制上皮可塑性的保守基因网络。我们鉴定了新的基因功能和网络模块，包括与Notch信号通路的串扰和染色质组织的调控，证明了在上皮重塑过程中重塑沃丁顿表观遗传景观的网络。直系同源功能TF靶标的表达区分了乳腺癌分子亚型并预测了新的肿瘤生物学特性，对精准医学具有启示意义。使用一个易于处理的细胞模型验证了预测的侵袭作用，支持了我们的方法。
