Authors
Servaas, N. H., Bauersachs, H. G., Abreu, L., Claringbould, A., Berest, I., Schwarz, J. J., Stein, F., Faelth-Savitski, M., Eismann, L., Reddington, J. P., Zaugg, J. B.
Abstract
CD4 T cell differentiation is orchestrated by coordinated signaling, transcriptional, and epigenomic programs, yet how signaling connects to chromatin and genetic variation in human T cells remains unclear. Here, we generated an integrative multi-omics map of human CD4 T cell activation and differentiation, combining phosphoproteomics, transcriptomics, and chromatin accessibility under Th0, Th1, and iTreg polarization. Within 10 minutes of activation, we observed rapid phosphorylation changes of RNA-binding proteins accompanied by degradation of effector-associated transcripts, preceding chromatin remodeling and later transcriptional activation of the same genes. Moreover, our data highlights how site-specific phosphorylation refines TF activity during T cell differentiation and activation, and identifies CDK1 as a regulator of Th1 effector function. Indeed, we found that a low dose of CKD1 inhibition impairs IFN-{gamma} expression and pro-inflammatory differentiation, while preserving regulatory features in iTregs. Single-cell multi-omic profiling upon CDK1 inhibition revealed how CDK1 activity shapes subset-specific gene regulatory networks, which are enriched for genetic variants associated with immune-traits. Specifically, CDK1-sensitive TFs, including IRF8, connect immune trait heritability to enhancer accessibility at IFNG and TNF loci. Together, these results establish CDK1 as a signaling hub that couples phosphorylation to gene regulation and genetic risk, with therapeutic relevance in autoimmune disease.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 01 Nov 2025.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 51
- Comments 0