Biology subjects

Jones, D. M.

Publications and source records attributed to Jones, D. M..

8 recordsLinked to original sources

bioRxiv2025

Aiolos restricts the generation of antigen-inexperienced, virtual memory CD8+ T cells

CD8+ virtual memory T (TVM) cells are memory-like cells that rapidly respond to infection via antigen-independent bystander effector functions. While it is recognized that TVM cells arise independently of foreign antigen encounter, the mechanisms governing their development are not fully understood. Here, we identify the transcription factor Aiolos as a negative regulator of TVM cells. We observed higher quantities of TVM cells in the spleens of uninfected Aiolos-deficient (Ikzf3-/-) mice relative to wild-type (WT). Furthermore, Ikzf3-/- TVM cells produced higher levels of IFN-{gamma} and granzyme B. In addition, we found that Ikzf3-/- TVM cells accumulated to higher quantities in the lungs within 24 hours of influenza virus infection. In line with enhanced TVM functional capacity and lung trafficking, Aiolos-deficient mice cleared virus more rapidly and exhibited reduced morbidity relative to WT animals. Mechanistically, we observed that Aiolos represses the TVM transcriptional regulator Eomes and the IL-15R subunit CD122 (IL-15R{beta}/IL-2R{beta}), known contributors of TVM cell generation. Collectively, these findings establish Aiolos as a novel molecular repressor of TVM generation and function.

immunology↗

bioRxiv2025

PRMT activity promotes global 3' UTR shortening in proliferating cells

Protein methyltransferase (PRMT)-catalysed arginine methylation is a widespread post-translational modification that regulates numerous RNA-binding proteins and frequently becomes dysregulated in cancer. While PRMT inhibitors have shown promise as an anti-cancer strategy, greater understanding of the downstream pathways linking arginine methylation to tumour-promoting phenotypes is needed to improve patient stratification and develop more effective therapeutic approaches. Here, we reveal arginine methylation as a critical regulator of alternative polyadenylation (APA) patterns that are fundamental to tumour progression. 3' RNA-sequencing assays uncover a rapid and global shift toward longer 3' UTR isoforms upon dual (symmetric and asymmetric) methylation (DMAi), impacting a broad range of cellular proliferation and signalling genes. Arginine methylation is required for sustaining proximal poly(A) site usage under high proliferative demand, as DMAi treatment blocks use of such sites in activated T cells, various cancer cell lines and patient-derived lung organoids. DMAi also counteracts the 3' UTR shortening caused by reduced CFIM25 expression, which normally promotes oncogenic isoforms. DMAi treatment affects APA in many of the same mRNAs as impaired cleavage and polyadenylation activity, and these mRNAs contain characteristic signatures such as high GC-content and long 3 UTRs. This systematic impact of PRMT activity on APA regulation broadens the potential utility of PRMT inhibitors as therapeutic agents for both cancer and immune-related diseases.

molecular biology↗

bioRxiv2024

Integrative analysis of higher-order transcriptome organisation and RNA condensation principles

Complex RNA-protein networks play a pivotal role in the formation of many types of biomolecular condensates. How intrinsic RNA features contribute to condensate formation however remains unclear. Here, we integrate tailored transcriptomics assays to identify a distinct class of developmental condensation-prone RNAs termed smOOPs (semi-extractable, orthogonal organic phase separation-enriched RNAs). These transcripts are localised to larger intracellular foci, form denser RNA-RNA interaction subnetworks than expected and are heavily bound by RNA binding proteins (RBPs). Using an explainable deep learning framework, we reveal that smOOPs harbor characteristic sequence composition with lower sequence complexity, increased intramolecular folding and specific RBP binding patterns. Intriguingly, these RNAs encode proteins bearing extensive intrinsically disordered regions and are markedly predicted to be involved in biomolecular condensates, indicating an interplay between RNA- and protein-based features in phase separation. This work advances our understanding of condensation-prone RNAs and provides a versatile resource to further investigate RNA-driven condensation principles.

molecular biology↗

bioRxiv2023

Flow: a web platform and open database to analyse, store, curate and share bioinformatics data at scale

Ever-increasing volumes of sequencing data offer potential for large-scale meta-analyses to address significant biological questions. However, challenges such as insufficient data processing information, data quality concerns, and issues related to accessibility and curation often present obstacles. Additionally, most experimental biologists lack the time and expertise needed to independently analyse, manage and share their own data. To overcome these hurdles, we present Flow, a web-based platform that links bioinformatic analysis and database solutions with a user-friendly interface and web API. Flow currently accommodates a range of genomics methods and further DSL2-compliant Nextflow pipelines can be added via a simple JSON schema file. Deployable on local systems or cloud services, an instance is freely accessible to academic researchers at https://flow.bio.

bioinformatics↗

bioRxiv2022

Eos promotes TH2 differentiation by propagating the IL-2/STAT5 signaling pathway.

The Ikaros zinc finger transcription factor Eos has been commonly implicated in regulatory T cells to promote their immunosuppressive functions. Paradoxically, a new role is emerging for Eos in promoting pro-inflammatory responses of conventional CD4+ T cells in the dysregulated setting of autoimmunity. Even so, the precise role of Eos in regulating the differentiation and function of healthy effector CD4+ T cell subsets remains unclear. Here, we find that Eos is a positive regulator of CD4+ T helper 2 (TH2) cells--effector T cells implicated in the induction of allergic asthma. Using murine in vitro TH2 cells and an in vivo house dust mite asthma model, we found that Eos-deficient T cells had reduced expression of key TH2 transcription factors, effector cytokines, and differentiation receptors. Mechanistically, among various TH2-polarizing pathways, the IL-2/STAT5 axis and its downstream TH2 gene targets emerged as one of the most significantly downregulated networks in Eos deficiency. Using in vitro TH2 cells and overexpression of Eos zinc-finger-domain mutants, we discovered that Eos forms a novel complex with and supports the tyrosine-phosphorylated signaling activity of STAT5. Overall, these data define a novel regulatory mechanism whereby Eos promotes IL-2/STAT5 activity to facilitate TH2 differentiation.

immunology↗

bioRxiv2022

OxoScan-MS: Oxonium ion scanning mass spectrometry facilitates plasma glycoproteomics in large scale

Protein glycosylation is a complex and heterogeneous post-translational modification. Specifically, the human plasma proteome is rich in glycoproteins, and as protein glycosylation is frequently dysregulated in disease, glycoproteomics is considered an underexplored resource for biomarker discovery. Here, we present OxoScan-MS, a data-independent mass spectrometric acquisition technology and data analysis software that facilitates sensitive, fast, and cost-effective glycoproteome profiling of plasma and serum samples in large cohort studies. OxoScan-MS quantifies glycosylated peptide features by exploiting a scanning quadrupole to assign precursors to oxonium ions, glycopeptide-specific fragments. OxoScan-MS reaches a high level of sensitivity and selectivity in untargeted glycopeptide profiling, such that it can be efficiently used with fast microflow chromatography without a need for experimental enrichment of glycopeptides from neat plasma. We apply OxoScan-MS to profile the plasma glycoproteomic in an inpatient cohort hospitalised due to severe COVID-19, and obtain precise quantities for 1,002 glycopeptide features. We reveal that severe COVID-19 induces differential glycosylation in disease-relevant plasma glycoproteins, including IgA, fibrinogen and alpha-1-antitrypsin. Thus, with OxoScan-MS we present a strategy for quantitatively mapping glycoproteomes that scales to hundreds and thousands of samples, and report glycoproteomic changes in severe COVID-19.

systems biology↗

bioRxiv2022

Aiolos modulates the TFH and CD4-CTL differentiation programs via reciprocal regulation of the Zfp831/TCF-1/Bcl-6 axis and CD25

Effective immunity to influenza virus and other respiratory viruses requires the generation of CD4+ T cell subsets that coordinate multiple aspects of the immune response. These subsets include T follicular helper (TFH) and T helper 1 (TH1) cells, which promote humoral and cell-mediated responses, respectively. A third population, CD4+ cytotoxic T lymphocytes (CD4-CTLs) facilitates clearance of infection via mechanisms normally associated with CD8+ T cells. Here, we identify the transcription factor Aiolos as a regulator of TFH and CD4-CTL responses. We demonstrate that Aiolos deficiency compromises TFH differentiation and antibody production during influenza virus infection. Conversely, we find that CD4+ T cells acquire a cytotoxic-like program in the absence of Aiolos, including increased expression of the CTL-associated transcription factors Eomes and Blimp-1. We further show that while Aiolos positively regulates the TFH transcriptional regulators Zfp831, TCF-1 and Bcl-6, it also directly represses expression of IL-2R and IL-2/STAT5-driven expression of the cytotoxic gene program. Thus, our findings identify Aiolos as a pivotal regulator of TFH and CD4-CTL differentiation and highlight its potential as a target for manipulating CD4+ T cell humoral and cytotoxic responses.

immunology↗

bioRxiv2019

Enhanced TF binding site maps improve regulatory networks learned from accessible chromatin data

Determining where transcription factors (TF) bind in genomes provides insights into which transcriptional programs are active across organs, tissue types, and environmental conditions. Recent advances in high-throughput profiling of regulatory DNA have yielded large amounts of information about chromatin accessibility. Interpreting the functional significance of these datasets requires knowledge of which regulators are likely to bind these regions. This can be achieved by using information about TF binding preferences, or motifs, to identify TF binding events that are likely to be functional. Although different approaches exist to map motifs to DNA sequences, a systematic evaluation of these tools in plants is missing. Here we compare four motif mapping tools widely used in the Arabidopsis research community and evaluate their performance using chromatin immunoprecipitation datasets for 40 TFs. Downstream gene regulatory network (GRN) reconstruction was found to be sensitive to the motif mapper used. We further show that the low recall of FIMO, one of the most frequently used motif mapping tools, can be overcome by using an Ensemble approach, which combines results from different mapping tools. Several examples are provided demonstrating how the Ensemble approach extends our view on transcriptional control for TFs active in different biological processes. Finally, a new protocol is presented to efficiently derive more complete cell type-specific GRNs through the integrative analysis of open chromatin regions, known binding site information, and expression datasets.

bioinformatics↗