Biology subjects

Chin, P.

Publications and source records attributed to Chin, P..

5 recordsLinked to original sources

bioRxiv2026

Intestinal bacteria hijack an evolutionarily conserved epithelial repair signal

Apoptosis in the gut triggers an expansion in the Enterobacteriaceae family of bacteria, causing both prolonged tissue injury and delayed repair. However, the mechanisms linking the Enterobacteriaceae bloom and subsequent deleterious tissue response are relatively unknown. Here, we establish purines as a major component of the apoptotic secretome that are consumed by bacteria. Explicitly, we identify hypoxanthine as a critical metabolite that is taken up and metabolised by both pathogenic and commensal species within the Enterobacteriaceae family. Epithelial cells release hypoxanthine into the extracellular space during early stages of apoptosis via the upregulation of equilibrative nucleoside transporters 1/2 (ENT1/2). Critically, beyond simply linking host and microbe, we delineate a connection between the release of hypoxanthine from the dying cell and the ability of the host to repair damaged epithelial tissue. Hypoxanthine is a potent promoter of epithelial cell repair in both gut and skin across the phylogenetic tree including humans, mice, zebrafish, and fruit flies and promotes similar ATP production and cellular proliferation in eukaryotic and microbial recipients. Thus, the preferential utilisation of hypoxanthine by the Enterobacteriaceae directly competes with the host for a core reparative signal.

microbiology↗

bioRxiv2025

Control of retrotransposon-driven activation of the interferon response by the double-stranded RNA binding protein DGCR8

The type I interferon (IFN) response is the main innate immune pathway against viruses in mammals. This pathway must be tightly regulated to prevent viral spread while avoiding excessive immune responses. Here, we show that inactivation of the double-stranded RNA (dsRNA)-binding protein DGCR8 unleashes the IFN response in human cells. We demonstrate that DGCR8 restricts the accumulation of endogenous dsRNA originating from protein-coding mRNAs that harbour transposable elements (TEs), primarily Alu. We propose that DGCR8 binding to TE-rich mRNAs is essential to resolve dsRNA structures, and in its absence, accumulated dsRNA signals through the RIG-I-like signalling pathway triggering the IFN response. This mechanism is relevant to conditions where DGCR8 expression levels are altered, including the 22q11.2 deletion syndrome (22qDS). Supporting this, we show that 22qDS-derived cells exhibit an exacerbated type I IFN response which inversely correlated with DGCR8 levels. All these together demonstrate the importance of suppressing endogenous TE-dsRNA accumulation to prevent unwanted immune activation and associated disease pathogenesis.

molecular biology↗

bioRxiv2024

Spatial programming of fibroblasts promotes resolution of tissue inflammation through immune cell exclusion

The role of fibroblasts in determining tissue topography and immune cell organisation within chronically inflamed tissues is poorly understood. Herein, we use multi-omic spatial analysis to define the cellular zonation pattern of the synovium in patients with inflammatory arthritis, identifying discrete tissue niches underpinned by spatially programmed subsets of synovial fibroblasts. We observe that perivascular fibroblasts switch on distinct matrix programs in response to cytokine signalling from neighbouring cells, forming adapted tissue niches that either permit or restrict immune cell trafficking. Specifically, IFN-{gamma}-responsive fibroblasts form a pathogenic lymphocyte-permissive niche that supports the persistence of leukocytes in the tissue, whilst TGF-{beta}-responsive, matrix-synthesising fibroblasts comprise a reparative niche, composed of a collagen-rich barrier around blood vessels that restricts leukocyte migration and promotes resolution of tissue inflammation. Augmentation of such endogenous pathways to promote resolution of inflammation may offer therapeutically tractable approaches for restoration of tissue homeostasis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/614064v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1e6e4dborg.highwire.dtl.DTLVardef@1baee04org.highwire.dtl.DTLVardef@1608a1forg.highwire.dtl.DTLVardef@10c1edb_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG

immunology↗

bioRxiv2024

DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects

The 22q11.2 deletion syndrome (22qDS) is caused by a microdeletion in chromosome 22, including DGCR8, an essential gene for miRNA production. The contribution of human DGCR8 hemizygosity to the disease is still unclear. In this study, we generated two human pluripotent cell models containing a single functional DGCR8 allele to elucidate its role on 22qDS. DGCR8+/-cells show increased apoptosis as well as self-renewal and differentiation defects in both the naive and primed states. The expression of primate-specific miRNAs was largely affected, due to impaired miRNA processing and chromatin accessibility. DGCR8+/- cells also displayed a pronounced reduction in human endogenous retrovirus class H (HERVH) expression, a primate-specific retroelement essential for pluripotency maintenance. Importantly, the reintroduction of primate-specific miRNAs as well as the miR-371-3 cluster rescued the cellular and molecular phenotypes of DGCR8+/-cells. Our results suggest that DGCR8 is haploinsufficient in humans and that miRNAs and transposable elements may have co-evolved in primates as part of an essential regulatory network to maintain stem cell identity.

molecular biology↗

bioRxiv2022

Improved And Optimized Drug Repurposing For The SARS-CoV-2 Pandemic

The active global SARS-CoV-2 pandemic caused more than 426 million cases and 5.8 million deaths worldwide. The development of completely new drugs for such a novel disease is a challenging, time intensive process. Despite researchers around the world working on this task, no effective treatments have been developed yet. This emphasizes the importance of drug repurposing, where treatments are found among existing drugs that are meant for different diseases. A common approach to this is based on knowledge graphs, that condense relationships between entities like drugs, diseases and genes. Graph neural networks (GNNs) can then be used for the task at hand by predicting links in such knowledge graphs. Expanding on state-of-the-art GNN research, Doshi et al. recently developed the Dr-COVID model. We further extend their work using additional output interpretation strategies. The best aggregation strategy derives a top-100 ranking of 8,070 candidate drugs, 32 of which are currently being tested in COVID-19-related clinical trials. Moreover, we present an alternative application for the model, the generation of additional candidates based on a given pre-selection of drug candidates using collaborative filtering. In addition, we improved the implementation of the Dr-COVID model by significantly shortening the inference and pre-processing time by exploiting data-parallelism. As drug repurposing is a task that requires high computation and memory resources, we further accelerate the post-processing phase using a new emerging hardware -- we propose a new approach to leverage the use of high-capacity Non-Volatile Memory for aggregate drug ranking.

bioinformatics↗