Understanding Disease Biology From A Functional Genomics Standpoint
Research in the Cribbs lab is directed towards understand disease biology from a functional genomics standpoint. We believe that advancing our understanding of the mechanisms that regulate genes, proteins and biological pathways will allow us to understand disease processes. Ultimately, our hope is that this will lead us to discovering novel therapeutic targets for treatment of disease. These goals are practised in highly collaborative projects, such as the Tendon Seed Network, Oxford-Bayer Alliance in Women’s health and Oxford Centre for Translational Myeloma research.
Nanopore sequencing of single-cell transcriptomes with scCOLOR-seq – Nature Biotechnology – Philpott et al, 2021
Here we describe single-cell corrected long-read sequencing (scCOLOR-seq), which enables error correction of barcode and unique molecular identifier oligonucleotide sequences and permits standalone cDNA nanopore sequencing of single cells. Barcodes and unique molecular identifiers are synthesized using dimeric nucleotide building blocks that allow error detection. We illustrate the use of the method for evaluating barcode assignment accuracy, differential isoform usage in myeloma cell lines, and fusion transcript detection in a sarcoma cell line.
A blood atlas of COVID-19 defines hallmarks of disease severity and specificity – Medrxiv – COMBAT Consortium, 2020
Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.
Histone H3K4me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism – PNAS – Cribbs et al, 2020
T cells control many immune functions, with Th17 cells critical in regulating inflammation. Following activation, T cells undergo metabolic reprogramming and utilize glycolysis to increase the ATP availability. Epigenetic mechanisms controlling metabolic functions in T cells are currently not well-defined. Here, we establish an epigenetic link between the histone H3K27me3 demethylases KDM6A/B and the coordination of a metabolic response. Inhibition of KDM6A/B leads to global increases in the repressive H3K27me3 histone mark, resulting in down-regulation of key transcription factors, followed by metabolic reprogramming and anergy. This work suggests a critical role of H3K27 demethylase enzymes in maintaining Th17 functions by controlling metabolic switches. Short-term treatment with KDM6 enzyme inhibitors may be useful in the therapy of chronic inflammatory diseases.