Biology subjects

Mein, C.

Publications and source records attributed to Mein, C..

3 recordsLinked to original sources

bioRxiv2024

The inflammatory micro-environment induced by targeted CNS radiotherapy is underpinned by disruption of DNA methylation

Although targeted radiotherapy (RT) is integral to the increasing survival of cancer patients, it has significant side-effects, the cellular and molecular mechanisms of which are not fully understood. During RT epigenetic changes occur in neoplastic tissue, but few studies have assessed these in non-neoplastic tissue and results are highly variable. Using bulk DNA methylation and RNA sequencing as well as spatial transcriptomics (ST) in a unique cohort of patient tissue samples, we show distinct differences in DNA methylation patterns in irradiated brain tissue, whilst ST characterisation identifies specific micro-environmental niches present after irradiation and highlights neuropeptides that could be propagating neuroinflammation. We also show that in a cerebral organoid (CO) model of early changes in neurons after irradiation there are similar DNA methylation alterations and disruption of the DNA methylation machinery, suggesting that early but persistent epigenetic dysregulation plays a role in neurotoxicity. We provide a link between radiotherapy induced neuroinflammation and disruption of DNA methylation for the first time and suggest possible driving mechanisms for this chronic neuroinflammation.

neuroscience↗

bioRxiv2024

Mapping chromatin remodelling in glioblastoma identifies epigenetic regulation of key molecular pathways and novel druggable targets.

Analysis of chromatin remodelling in neoplastic stem cells as compared to ontogenetically related neural stem cells, reveals multifactorial epigenetic regulation of signalling pathways known to contribute to glioblastoma development. It also identifies novel epigenetically regulated druggable target genes on a patient-specific level, including SMOX and GABBR2 which could be further developed for future translational approaches to more effectively treat this neoplasm.

cancer biology↗

bioRxiv2023

Transcriptomic profiling reveals a pro-nociceptive role for Angiotensin II in inflammatory bowel disease

ObjectiveVisceral pain is a leading cause of morbidity in inflammatory bowel disease (IBD), contributing significantly to reduced quality of life. Currently available analgesics often lack efficacy or have intolerable side-effects, driving the need for a more complete understanding of the mechanisms causing pain. MethodsWhole transcriptome gene expression analysis was performed by bulk RNA sequencing of colonic biopsies from patients with ulcerative colitis (UC) and Crohns disease (CD) reporting abdominal pain and compared with non-inflamed control biopsies. Putative pro-nociceptive mediators were identified based on pathway analysis of differentially expressed genes in IBD tissue and single cell gene expression in colonic neurons. Pro-nociceptive activity of identified mediators was assessed in assays of sensory neuron and colonic afferent activity. ResultsRNA sequencing analysis highlighted a 7.6-fold increase in the expression of angiotensinogen transcripts, Agt, the precursor to angiotensin II (Ang II), in samples from UC patients (p = 3.2x10-8). Consistent with the marked expression of the angiotensin AT1 receptor in colonic neurons, Ang II elicited an increase in intracellular Ca2+ in capsaicin-sensitive, voltage gated sodium channel subtype NaV1.8-positive sensory neurons. Ang II also evoked action potential discharge in high-threshold colonic nociceptors. These effects were inhibited by the AT1 receptor antagonist valsartan. ConclusionFindings from our study identify AT1 receptor-mediated colonic nociceptor activation as a novel pathway of visceral nociception in IBD patients with UC. This work highlights the potential utility of angiotensin receptor blockers, such as valsartan, as treatments for pain in IBD.

neuroscience↗