Palani Santhosh, Sarkar Casim A
Department of Bioengineering and Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6321, USA.
Biophys J. 2008 Aug;95(4):1575-89. doi: 10.1529/biophysj.107.120600. Epub 2008 May 9.
Cytokines and lineage-specific transcription factors are critical molecular effectors for terminal differentiation during hematopoiesis. Intrinsic transcription factor activity is often believed to drive commitment and differentiation, whereas cytokine receptor signals have been implicated in the regulation of cell proliferation, survival, and differentiation. In erythropoiesis, recent experimental findings provide direct evidence that erythropoietin (Epo) can generate commitment cues via the erythropoietin receptor (EpoR); specifically, EpoR signaling leads to activation of the transcription factor GATA-1, which then triggers transcription of erythrocyte-specific genes. In particular, activated GATA-1 induces two positive feedback loops in the system through the enhanced expression of both inactive GATA-1 and EpoR, the latter of which is externally regulatable by Epo. Based upon this network architecture, we present a mathematical model of GATA-1 activation by EpoR, which bidirectionally links a lineage-specific receptor and transcription factor. Our deterministic model offers insight into stimulus-response relationships between Epo and several downstream effectors. In addition to the survival signals that EpoR provides, steady-state analysis of our model suggests that receptor upregulation during lineage commitment can also generate ultrasensitivity to Epo and bistability in GATA-1 activity. These system-level properties can induce a switch-like characteristic during differentiation and provide robustness to the mature state. The topology also suggests a novel mechanism for achieving robust bistability in a purely deterministic manner without molecular cooperativity. The analytical solution of a generalized, minimal model is provided and the significance of each of the two positive feedback loops is elucidated through bifurcation analysis. This network topology, or variations thereof, may link other receptor-transcription factor pairs and may therefore be of general relevance in cellular decision-making.
细胞因子和谱系特异性转录因子是造血过程中终末分化的关键分子效应物。人们通常认为内在转录因子活性驱动细胞定向分化和分化过程，而细胞因子受体信号则参与细胞增殖、存活和分化的调控。在红细胞生成过程中，最近的实验结果提供了直接证据，表明促红细胞生成素（Epo）可通过促红细胞生成素受体（EpoR）产生定向分化信号；具体而言，EpoR信号传导导致转录因子GATA-1激活，进而触发红细胞特异性基因的转录。特别是，激活的GATA-1通过增强无活性GATA-1和EpoR的表达在系统中诱导两个正反馈回路，其中后者可由Epo进行外部调节。基于这种网络结构，我们提出了一个EpoR激活GATA-1的数学模型，该模型双向连接了一个谱系特异性受体和转录因子。我们的确定性模型深入探讨了Epo与几种下游效应物之间刺激-反应关系。除了EpoR提供的存活信号外，我们模型的稳态分析表明，谱系定向过程中受体上调还可产生对Epo的超敏感性和GATA-1活性的双稳态。这些系统水平特性可在分化过程中诱导类似开关的特性，并为成熟状态提供稳健性。该拓扑结构还提出了一种以纯确定性方式实现稳健双稳态而无需分子协同作用的新机制。提供了一个广义最小模型的解析解，并通过分岔分析阐明了两个正反馈回路各自的意义。这种网络拓扑结构或其变体可能连接其他受体-转录因子对，因此可能在细胞决策中具有普遍相关性。
