Department of Biosystems Science & Engineering, Eidgenössische Technische Hochschule Zürich, Basel, Switzerland.
Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
J Exp Med. 2022 Jan 3;219(1). doi: 10.1084/jem.20202490. Epub 2021 Nov 24.
Transcription factors (TFs) regulate cell fates, and their expression must be tightly regulated. Autoregulation is assumed to regulate many TFs' own expression to control cell fates. Here, we manipulate and quantify the (auto)regulation of PU.1, a TF controlling hematopoietic stem and progenitor cells (HSPCs), and correlate it to their future fates. We generate transgenic mice allowing both inducible activation of PU.1 and noninvasive quantification of endogenous PU.1 protein expression. The quantified HSPC PU.1 dynamics show that PU.1 up-regulation occurs as a consequence of hematopoietic differentiation independently of direct fast autoregulation. In contrast, inflammatory signaling induces fast PU.1 up-regulation, which does not require PU.1 expression or its binding to its own autoregulatory enhancer. However, the increased PU.1 levels induced by inflammatory signaling cannot be sustained via autoregulation after removal of the signaling stimulus. We conclude that PU.1 overexpression induces HSC differentiation before PU.1 up-regulation, only later generating cell types with intrinsically higher PU.1.
转录因子 (TFs) 调节细胞命运，其表达必须受到严格调控。自调控被认为可以调节许多 TF 自身的表达，以控制细胞命运。在这里，我们操纵和量化了控制造血干细胞和祖细胞 (HSPCs) 的 TF PU.1 的（自）调控，并将其与它们未来的命运相关联。我们生成了转基因小鼠，允许诱导性激活 PU.1 和非侵入性量化内源性 PU.1 蛋白表达。量化的 HSPC PU.1 动力学表明，PU.1 的上调是造血分化的结果，而不依赖于直接的快速自调控。相比之下，炎症信号诱导快速的 PU.1 上调，这不需要 PU.1 表达或其与自身自调控增强子的结合。然而，炎症信号诱导的增加的 PU.1 水平在去除信号刺激后不能通过自调控来维持。我们得出结论，PU.1 过表达在 PU.1 上调之前诱导 HSC 分化，只有在这之后才会产生内在具有更高 PU.1 水平的细胞类型。
