Biology subjects

Bauersachs, H. G.

Publications and source records attributed to Bauersachs, H. G..

2 recordsLinked to original sources

bioRxiv2025

Integrative Multi-Omics Identifies CDK1 as a Key Signaling Regulator of CD4+ T Cell Effector Function

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.

genomics↗

bioRxiv2023

Scalable ultra-high-throughput single-cell chromatin and RNA sequencing reveals gene regulatory dynamics linking macrophage polarization to autoimmune disease

Enhancers and transcription factors (TFs) are crucial in regulating cellular processes, including disease-associated cell states. Current multiomic technologies to study these elements in gene regulatory mechanisms lack multiplexing capability and scalability. Here, we present SUM-seq, a cost-effective, scalable Single-cell Ultra-high-throughput Multiomic sequencing method for co-assaying chromatin accessibility and gene expression in single nuclei. SUM-seq enables profiling hundreds of samples at the million cell scale and outperforms current high-throughput single-cell methods. We applied SUM-seq to dissect the gene regulatory mechanisms governing macrophage polarization and explored their link to traits from genome-wide association studies (GWAS). Our analyses confirmed known TFs orchestrating M1 and M2 macrophage programs, unveiled key regulators, and demonstrated extensive enhancer rewiring. Integration with GWAS data further pinpointed the impact of specific TFs on a set of immune traits. Notably, inferred enhancers regulated by the STAT1/STAT2/IRF9 (ISGF3) complex were enriched for genetic variants associated with Crohns disease, ulcerative colitis and multiple sclerosis, and their target genes included known drug targets. This highlights the potential of SUM-seq for dissecting molecular disease mechanisms. SUM-seq offers a cost-effective, scalable solution for ultra-high-throughput single-cell multiomic sequencing, excelling in unraveling complex gene regulatory networks in cell differentiation, responses to perturbations, and disease studies.

genomics↗