TNF-induced gene expression oscillates in time

Abstract

With only few exceptions that include Hes-1 p53, and IκB, the expression of genes has never been shown to be oscillatory. Here, we show that the inflammatory cytokine TNF triggers oscillations in >5000 genes. We utilize microarrays at 30-min intervals to analyze the pattern of global gene expression in murine macrophages. We find that 15% of genes in the genome underwent a significant >3-fold increase in expression, with 89% of these displaying oscillations at frequencies as low as every 50 min. We analyze further two sub-clusters of genes that either began oscillating early or after a lag phase. Through the use of quantitative PCR, we confirm the oscillations and show that the oscillations are continuous. Moreover, we show that these continuous oscillations are not unique to TNF, but that related cytokines such as RANK-L produces oscillations with a unique induction profile. In the two papers accompanying this one, we analyze the mechanism of these oscillations and find that TNF also triggers oscillations in the phosphorylation of MAP kinases, and that these oscillations combine to recruit transcription factors to promoters in a cyclical fashion. The results presented here suggest that gene transcription is a highly dynamic processes, with thousands of genes displaying rapid (<60 min) oscillations over time. Considering this dynamism, time-resolved measurements of gene transcription should become the experimental norm.