CARTOGRAPHY – The human transcription factor landscape at single cell resolution

LEAD SUPERVISOR:  Prof Holm Uhlig, Nuffield Department of Medicine

Co-supervisor: Dr Calli Dendrou, Nuffield Department of Medicine

Commercial partner: Janssen R&D, UK

Immune-mediated disorders (IMDs) such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis affect a large proportion of the population. Genetic association studies, functional studies, and clinical observations suggest not only disease specific features but also a substantial mechanistic overlap between inflammatory disorders affecting different organ systems. This is reflected by the response towards therapies across different IMDs (e.g. anti-TNF, anti-IL12/23, JAK-STAT inhibitors). One essential problem is whether there are inflammatory or anti-inflammatory cellular response modules that can be used as a diagnostic marker and therapeutically targeted. Single-cell technologies have revolutionized our understanding of organ development, physiology and pathology. However, transcriptional regulatory modules are of the characterized indirectly, particularly because transcription factor gene expression is not typically well captured and single cell proteomic data focus on membrane proteins.

We will overcome this hurdle by complementing exomewide 10x single-cell transcriptomic as well as Cite-seq technology with targeted single-cell expression analysis of all high-confidence transcription factors found in the human genome. A targeted panel will link the transcription factor expression with cell type, lineage commitment, activation status, tissue specificity and disease. Combining this transcription factor profiling with computational tools for inferring transcription factor binding sites and integrating data on chromatin accessibility and long read transcriptomics to cover isoforms, we will also determine the downstream genes modulated by the transcription factors to establish regulatory networks. We will benchmark this map of transcription machinery based on known regulatory networks and establish this comprehensive single cell resolution TF atlas across organs (gut, skin, joint, blood and bone marrow) in immune cells, as well as stroma cells, epithelial cells and endothelial cells.

The proposed DPhil project will be integrated into the Oxford-Janssen Cartography project which aims to apply the latest molecular and cellular multi-omics analysis platforms to deliver insights for target selection and precision medicine across IMDs where existing options for therapeutic intervention are limited.

Apply using course: DPhil in Clinical Medicine