Biology subjects

Jarman, E.

Publications and source records attributed to Jarman, E..

3 recordsLinked to original sources

bioRxiv2025

JMJD5 regulates metabolism by inhibiting the Arginine Methyltransferase PRMT6

2-Oxoglutarate-dependent dioxygenases (2OGDDs) employ molecular oxygen, 2-oxoglutarate, and ferrous iron to catalyse two-ectron oxidations. This dependency enables some 2OGDD to act as sensors of cellular metabolic states, driving crucial functions when oxygen or metabolic homeostasis is perturbed, including adaptation to low oxygen, epigenetic control of gene transcription, and the reshaping of metabolic pathways. Jumonji-C (JmjC) domain-containing protein 5 (JMJD5), a 2OGDD that regulates epigenetic marks, is essential for DNA damage repair and is a key regulator of cell metabolism. Notably, JMJD5 is often reduced in hepatocellular carcinoma, correlating with poor overall survival. Despite its biological significance, the molecular functions of JMJD5 remain unresolved, and its physiological targets are elusive. Here, we identify and characterise a novel signalling pathway where JMJD5 hydroxylates an arginine residue on the protein ISY1. This modification enables ISY1 to bind to and reduce the activity of Protein Arginine N-methyltransferase 6 (PRMT6). Significantly, the inactivation of PRMT6 rescues the majority of the molecular phenotype driven by JMJD5 loss, establishing the JMJD5-ISY1-PRMT6 pathway as a principal executor of JMJD5s enzymatic function. In a genetically engineered murine liver cancer model, JMJD5 loss suppressed tumour growth and rewired one-carbon, amino acid, and lipid metabolism, recapitulating the network-level changes observed in human HCC cells. This signalling pathway clarifies existing controversies regarding JMJD5s function and identifies PRMT6 as a potential therapeutic target for treating cancers that lack JMJD5.

cell biology↗

bioRxiv2025

Perivascular matrix densification dysregulates angiogenesis and activates pro-inflammatory endothelial cells

Fibrosis is central to numerous fatal conditions including solid cancers, pulmonary fibrosis, cirrhosis and post-infarct cardiac fibrosis amongst many others, thereby collectively contributing to 45% of all deaths in developed nations. The potential for fibrosis across most organ systems may stem from its connections to wound healing and the ubiquitous presence of vascular endothelium. Endothelial cells (ECs) and angiogenesis, cells and associated biological program central to wound healing, have been heavily implicated in many organ-specific fibroses, but the relationship between angiogenesis and fibrogenesis remains debated and little has been established in terms of how the EC phenotype governs tissue healing vs. fibrosis. Here, we examine a murine lung injury model enabling EC lineage tracing and observe the invasion of aberrant ECs from the bronchial microvasculature following lung injury along with concurrent densification of matrix fibers surrounding these vessels. To investigate the underlying mechanisms governing their appearance, we established a microphysiological system (MPS) of arteriole/venule-scale microvessels embedded within a tunable stromal mimetic matrix and find that heightened extracellular matrix fiber density activates ECs, drives endothelial to mesenchymal transition, and promotes aberrant tip EC (ATEC) invasion into the matrix. ATECs remain adherent to fibrotic matrix and possess a pro-inflammatory phenotype that secretes TGF-{beta}2. Notably, our studies establish that the formation of ATECs is gated by destabilization of endothelial adherens junction upon EC adhesion to fibrous matrix, and associated regulation of TGF-{beta} signaling that is mediated by a novel VE-cadherin - TGF-{beta}R2 axis. The current lack of effective anti-fibrotic therapies suggests potential critical involvement of other cell types such as ECs, and our findings suggest new contributions of ECs to fibrotic progression that may better inform future targets for novel anti-fibrotic therapeutics.

bioengineering↗

bioRxiv2021

In vivo modelling of patient genetic heterogeneity identifies concurrent Wnt and PI3K activity as a potent driver of invasive cholangiocarcinoma growth.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy of the bile ducts within the liver characterised by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult and developing modes of patient stratification and targeted therapies remains challenging. As a result, survival rates following a diagnosis with ICC have remained static since the late 1970s, whilst incidence of ICC has increased. Here, we performed the first functional in vivo study into the role that genetic heterogeneity plays in drivinga ICC via modelling of interactions between rare mutations with more common driver genes. By leveraging human ICC sequencing data to stratify and then model genetic heterogeneity in the mouse, we uncovered numerous novel tumour suppressors which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. In this study, we specifically focus on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC. We show that tumour growth of this cancer relies on both Wnt and PI3K signalling to drive proliferation and suppress apoptosis. Finally, we demonstrate that pharmacological co-inhibition of Wnt and PI3K in vivo substantially impedes the growth of ICC, regardless of mutational profile. As such, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment and inhibitors of these pathways should be levied as a treatment for patients diagnosed with ICC.

cancer biology↗