Characterizing Dynamic Changes in the Human Blood Transcriptional Network

Abstract

Gene expression data generated systematically in a given system over multiple time points provides a source of perturbation that can be leveraged to infer causal relationships among genes explaining network changes. Previously, we showed that food intake has a large impact on blood gene expression patterns and that these responses, either in terms of gene expression level or gene-gene connectivity, are strongly associated with metabolic diseases. In this study, we explored which genes drive the changes of gene expression patterns in response to time and food intake. We applied the Granger causality test and the dynamic Bayesian network to gene expression data generated from blood samples collected at multiple time points during the course of a day. The simulation result shows that combining many short time series together is as powerful to infer Granger causality as using a single long time series. Using the Granger causality test, we identified genes that were supported as the most likely causal candidates for the coordinated temporal changes in the network. These results show that PER1 is a key regulator of the blood transcriptional network, in which multiple biological processes are under circadian rhythm regulation. The fasted and fed dynamic Bayesian networks showed that over 72% of dynamic connections are self links. Finally, we show that different processes such as inflammation and lipid metabolism, which are disconnected in the static network, become dynamically linked in response to food intake, which would suggest that increasing nutritional load leads to coordinate regulation of these biological processes. In conclusion, our results suggest that food intake has a profound impact on the dynamic co-regulation of multiple biological processes, such as metabolism, immune response, apoptosis and circadian rhythm. The results could have broader implications for the design of studies of disease association and drug response in clinical trials.

Author Summary

Peripheral blood is the most readily accessible human tissue for clinical studies and experimental research more generally. Large-scale molecular profiling technologies have enabled measurements of mRNA expression on the scale of whole genomes. Understanding the relationships between human blood gene expression profiles and clinical traits is extremely useful for inferring causal factors for human disease and for studying drug response. Biological pathways and the complex behaviors they induce are not static, but change dynamically in response to external factors such as intake/uptake of nutrients and administration of drugs. We employed a randomized, two-arm cross-over design to assess the effects of fasting and feeding on the dynamic changes of blood transcriptional network. Our work has convincingly shown that feeding or increasing nutritional load affects the human circadian rhythm system which connects to other biological processes including metabolic and immune responses. We believe this is a first step towards a more comprehensive population-based study that seeks to connect changes in the blood transcriptome to drug response, and to disease and biology more generally.