Intracellular Information Processing through Encoding and Decoding of Dynamic Signaling Features.
Intracellular Information Processing through Encoding and Decoding of Dynamic Signaling Features.
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DOI：
10.1371/journal.pcbi.1004563
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发表时间：
2015-10
影响因子：
4.3
通讯作者：
Vadigepalli R
中科院分区：
文献类型：
--
作者：
Makadia HK;Schwaber JS;Vadigepalli R
Cell signaling dynamics and transcriptional regulatory activities are variable within specific cell types responding to an identical stimulus. In addition to studying the network interactions, there is much interest in utilizing single cell scale data to elucidate the non-random aspects of the variability involved in cellular decision making. Previous studies have considered the information transfer between the signaling and transcriptional domains based on an instantaneous relationship between the molecular activities. These studies predict a limited binary on/off encoding mechanism which underestimates the complexity of biological information processing, and hence the utility of single cell resolution data. Here we pursue a novel strategy that reformulates the information transfer problem as involving dynamic features of signaling rather than molecular abundances. We pursue a computational approach to test if and how the transcriptional regulatory activity patterns can be informative of the temporal history of signaling. Our analysis reveals (1) the dynamic features of signaling that significantly alter transcriptional regulatory patterns (encoding), and (2) the temporal history of signaling that can be inferred from single cell scale snapshots of transcriptional activity (decoding). Immediate early gene expression patterns were informative of signaling peak retention kinetics, whereas transcription factor activity patterns were informative of activation and deactivation kinetics of signaling. Moreover, the information processing aspects varied across the network, with each component encoding a selective subset of the dynamic signaling features. We developed novel sensitivity and information transfer maps to unravel the dynamic multiplexing of signaling features at each of these network components. Unsupervised clustering of the maps revealed two groups that aligned with network motifs distinguished by transcriptional feedforward vs feedback interactions. Our new computational methodology impacts the single cell scale experiments by identifying downstream snapshot measures required for inferring specific dynamical features of upstream signals involved in the regulation of cellular responses. Single cell studies have shown that differential patterns in the dynamics of signaling proteins, transcription factor activity, gene expression, etc. produce distinct downstream outcomes. The opposite also holds true where particular cellular outcomes have been found to be associated with the dynamical pattern of one or more signaling molecules. Signaling pathways, therefore, serve as signal processing units to inform specific downstream regulation. However, the functional capabilities of the dynamic aspects of signaling are not well understood. To address this issue, we developed a new approach that evaluates information processing between dynamic features in signaling patterns and transcriptional regulatory activity. Our work demonstrates that the information transfer occur through decoding of temporal history of signals rather than only through instantaneous correlations. Moreover, our results identify regulatory network motifs as the critical components in the information processing and filtering of variability in signaling dynamics to produce distinct patterns of downstream transcriptional responses. Our methodology can be broadly applied to single cell scale data on experimentally accessible downstream measures to infer dynamic aspects of upstream signaling.
影响因子：
16
作者：
Purvis, Jeremy E.;Lahav, Galit
通讯作者：
Lahav, Galit