Nrf1 and Nrf2, as two principal CNC-bZIP transcription factors, regulate similar but different targets involved in a variety of biological functions for maintaining cell homeostasis and organ integrity. Of note, the unique topobiological behavior of Nrf1 makes its functions more complicated than Nrf2, because it is allowed for alternatively transcribing and selectively splicing to yield multiple isoforms (e.g., TCF11, Nrf1α). In order to gain a better understanding of their similarities and differences in distinct regulatory profiles,all four distinct cell models for stably expressing TCF11, TCF11^ΔN, Nrf1α or Nrf2 have been herein established by an Flp-In™ T-REx™-293 system and then identified by transcriptomic sequencing. Further analysis revealed that Nrf1α and TCF11 have similar yet different regulatory profiles, although both contribute basically to positive regulation of their co-targets, which are disparate from those regulated by Nrf2. Such disparity in gene regulation by Nrf1 and Nrf2 was also corroborated by scrutinizing comprehensive functional annotation of their specific and/or common target genes. Conversely, the mutant TCF11^ΔN, resulting from a deletion of the N-terminal amino acids 2-156 from TCF11, resembles Nrf2 with largely consistent structure and function. Interestingly, our further experimental evidence demonstrates that TCF11 acts as a potent tumor-repressor relative to Nrf1α, albeit both isoforms possess a congruous capability to prevent malignant growth of tumor and upregulate those genes critical for improving the survival of patients with hepatocellular carcinoma.

中文翻译：

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通过定义相似但不同的调控特征，TCF11 比其原型 Nrf1α 具有更强的肿瘤抑制作用，与​​ Nrf2 存在显着差异

Nrf1 和 Nrf2 作为两个主要的 CNC-bZIP 转录因子，调节相似但不同的靶标，这些靶标涉及维持细胞稳态和器官完整性的各种生物学功能。值得注意的是，Nrf1 独特的拓扑生物学行为使其功能比 Nrf2 更复杂，因为它允许交替转录和选择性剪接以产生多种亚型（例如，TCF11、Nrf1α）。为了更好地了解它们在不同调节谱中的异同，所有四种不同的细胞模型均用于稳定表达 TCF11、TCF11 ^ΔN在本文中，Nrf1α 或 Nrf2 已通过 Flp-In™ T-REx™-293 系统建立，然后通过转录组测序进行鉴定。进一步的分析表明，Nrf1α 和 TCF11 具有相似但不同的调节特征，尽管它们基本上都有助于对其共同靶点的正调节，这与 Nrf2 调节的靶点不同。Nrf1 和 Nrf2 在基因调控中的这种差异也通过仔细检查其特定和/或共同靶基因的综合功能注释得到证实。相反，突变的 TCF11 ^ΔN由 TCF11 的 N 端氨基酸 2-156 缺失导致，类似于 Nrf2，具有基本一致的结构和功能。有趣的是，我们进一步的实验证据表明，TCF11 相对于 Nrf1α 而言是一种有效的肿瘤抑制因子，尽管这两种亚型都具有防止肿瘤恶性生长和上调那些对提高肝细胞癌患者存活率至关重要的基因的一致能力。