The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China; MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Innovation Academy for Seed Design, Chinese Academy of Sciences, Hefei, Anhui 230027, China.
MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Innovation Academy for Seed Design, Chinese Academy of Sciences, Hefei, Anhui 230027, China.
J Genet Genomics. 2023 May;50(5):305-317. doi: 10.1016/j.jgg.2023.01.006. Epub 2023 Jan 21.
Transcription factors (TFs) regulate cellular activities by controlling gene expression, but a predictive model describing how TFs quantitatively modulate human transcriptomes is lacking. We construct a universal human gene expression predictor named EXPLICIT-Human and utilize it to decode transcriptional regulation. Using the expression of 1613 TFs, the predictor reconstitutes highly accurate transcriptomes for samples derived from a wide range of tissues and conditions. The broad applicability of the predictor indicates that it recapitulates the quantitative relationships between TFs and target genes ubiquitous across tissues. Significant interacting TF-target gene pairs are extracted from the predictor and enable downstream inference of TF regulators for diverse pathways involved in development, immunity, metabolism, and stress response. A detailed analysis of the hematopoiesis process reveals an atlas of key TFs regulating the development of different hematopoietic cell lineages, and a portion of these TFs are conserved between humans and mice. The results demonstrate that our method is capable of delineating the TFs responsible for fate determination. Compared to other existing tools, EXPLICIT-Human shows a better performance in recovering the correct TF regulators.
转录因子 (TFs) 通过控制基因表达来调节细胞活动，但缺乏描述 TFs 如何定量调节人类转录组的预测模型。我们构建了一个名为 EXPLICIT-Human 的通用人类基因表达预测器，并利用它来解码转录调控。使用 1613 个 TFs 的表达，该预测器可以为来自广泛组织和条件的样本重新构建高度准确的转录组。该预测器的广泛适用性表明，它普遍再现了 TFs 和靶基因之间的定量关系。从预测器中提取出显著相互作用的 TF-靶基因对，并能够对参与发育、免疫、代谢和应激反应等多种途径的 TF 调节剂进行下游推断。对造血过程的详细分析揭示了调节不同造血细胞谱系发育的关键 TFs 的图谱，其中一部分 TFs 在人类和小鼠之间是保守的。结果表明，我们的方法能够描绘负责命运决定的 TFs。与其他现有工具相比，EXPLICIT-Human 在恢复正确的 TF 调节剂方面表现出更好的性能。
