Dynamic transcription factor activity networks in response to independently altered mechanical and adhesive microenvironmental cues.
Dynamic transcription factor activity networks in response to independently altered mechanical and adhesive microenvironmental cues.
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DOI：
10.1039/c6ib00093b
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发表时间：
2016-08-08
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影响因子：
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通讯作者：
Seidlits SK
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文献类型：
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作者：
Peñalver Bernabé B;Shin S;Rios PD;Broadbelt LJ;Shea LD;Seidlits SK
局部细胞外环境的多个方面深刻地影响细胞表型和功能。环境中的物理和化学信号触发细胞内信号级联，最终激活转录因子（TF）-细胞表型的强大调节因子。TRACER（转录活性细胞11a射线）用于在具有受控弹性模量和整联蛋白配体密度的水凝胶上培养的人成纤维细胞中TF活性的大规模动态定量。我们确定了三组TF：仅对配体密度、底物硬度或两者的改变有反应。通过计算构建了调节TF的动态网络，并揭示了不同的TF活性水平、方向性（即，激活或抑制），以及粘合剂和机械提示的动力学。此外，TRACER网络预测了多种细胞类型中TF活性的保守中心，这些中心在临床纤维化组织中发生了显著变化。我们的方法捕获粘附和机械刺激的不同和重叠的影响，确定在正常和疾病状态下保守的信号传导机制。
Multiple aspects of the local extracellular environment profoundly affect cell phenotype and function. Physical and chemical cues in the environment trigger intracellular signaling cascades that ultimately activate transcription factors (TFs) – powerful regulators of the cell phenotype. TRACER (TRanscriptional Activity CEll aRrays) was employed for large-scale, dynamic quantification of TF activity in human fibroblasts cultured on hydrogels with a controlled elastic modulus and integrin ligand density. We identified three groups of TFs: responders to alterations in ligand density alone, substrate stiffness or both. Dynamic networks of regulatory TFs were constructed computationally and revealed distinct TF activity levels, directionality (i.e., activation or inhibition), and dynamics for adhesive and mechanical cues. Moreover, TRACER networks predicted conserved hubs of TF activity across multiple cell types, which are significantly altered in clinical fibrotic tissues. Our approach captures the distinct and overlapping effects of adhesive and mechanical stimuli, identifying conserved signaling mechanisms in normal and disease states.