A temporal signaling code to specify immune responses

This talk will be presented online. Zoom link: 709 120 4849 (pw: 1234)

Abstract:

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.1-10

Decoding signaling codons to specify immune responses

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