A temporal signaling code to specify innate immune responses and memory

Prof. Alexander Hoffmann



Immune sentinel cells must initiate the appropriate immune response upon sensing the presence of diverse pathogens or immune stimuli. To generate stimulus-specific gene expression responses, immune sentinel cells have evolved a temporal code in the dynamics of stimulus responsive transcription factors. I will present recent works 1) using an information theoretic approach to identify the codewords, termed “signaling codons”, 2) using a machine learning approach to characterize their reliability and points of confusion, and 3) dynamical systems modeling to characterize the molecular circuits that allow for their encoding. I will present progress on how the temporal code may be decoded to specify immune responses. Further, I will discuss to what extent such a code may be harnessed to achieve greater pharmacological specificity when therapeutically targeting pleiotropic signaling hubs.

NFκB Signaling: information theory, signaling codons
Adelaja, A., Taylor, B., Sheu, K.M., Liu, Y., Luecke, S., Hoffmann, A. 2021 Six distinct NFκB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses. Immunity, 54, pp.916-930. e7. PMID: 33979588
Tang, Y., Adelaja, A., Ye, X, Deeds, E., Wollman, R., Hoffmann, A. 2021. Quantifying information accumulation encoded in the dynamics of biochemical signaling. Nature Communications 12, pp. pp.1272. PMID: 33627672, PMC7904837

Decoding signaling codons to specify immune response gene expression and epigenetic memory
Sen S., Cheng, Z., Sheu, K., Chen, E.Y.H., Hoffmann, A. 2020 Gene Regulatory Strategies that Decode the Duration of NFkB Dynamics Contribute to LPS- versus TNF-Specific Gene Expression. Cell Systems, 10, pp.1-14. PMID:31972132, PMC7047529
Cheng, Q.J., Ohta, S., Sheu, K.M., Spreafico, R., Adelaja, A., Taylor, B., Hoffmann, A. 2021 NFκB dynamics determine the stimulus-specificity of epigenomic reprogramming in macrophages. Science, 372, pp.1349-1353; PMID: 34140389.

Pharmacologic manipulation of the code
Behar, M., Barken, D., Werner, S.L., Hoffmann, A. 2013 The Dynamics of Signaling as a Pharmacological Target. Cell, 155, pp.448-461. PMID: 24120141, PMC3856316

Date: Oct. 27, 2021 (Wed) 10:00 – 11:30
Place: Zoom
Host: Shinya Kuroda

If you would like to attend, please email us at info.kuroda-lab [at] bs.s.u-tokyo.ac.jp and we will send you the Zoom URL. Please use your institution’s e-mail address and let us know your name and affiliation.