Biology subjects

Detroja, R.

Publications and source records attributed to Detroja, R..

3 recordsLinked to original sources

bioRxiv2025

Blood-based Epigenetic Instability Linked to Human Aging and Disease

The abundance, dynamics, and context-dependent heterogeneity of DNA methylation--where a pattern considered abnormal in one cell type may be normal in another--poses challenges in identifying methylation abnormalities linked to disease risk. Through genome-wide analyses, we identified CpG sites with remarkably consistent methylation profiles in healthy whole blood, predominantly existing in an unmethylated state. We examined alterations at these epigenetically stable loci in diverse cohorts, including those with cardiovascular disease and hematological cancers. Our findings reveal methylation pattern disruption in myeloid and lymphoid malignancies, correlating with clonal burden fluctuations during leukemia treatment. In non-cancer cohorts, we observed that normally stable CpG sites exhibited progressive instability with advancing age, which was also associated with the onset of cardiovascular disease and decreased survival rates. This study links DNA methylation instability with the expansion of risk-prone blood cells and highlights its role as a biomarker for both cancer and cardiovascular disease.

genetics↗

bioRxiv2022

tRNA Methylation Resolves Codon Usage Bias at the Limit of Cell Viability

The codon usage of each genome is closely correlated with the abundance of tRNA isoacceptors. How codon-usage bias is resolved by tRNA post-transcriptional modifications is largely unknown. Here we demonstrate that the N1-methylation of guanosine at position 37 (m1G37) on the 3-side of the anticodon, while not directly responsible for reading of codons, is a neutralizer that resolves differential decoding of proline codons. A genome-wide suppressor screen of a non-viable E. coli strain, m1G37-lacking, identifies proS suppressor mutations, indicating a coupling of methylation with tRNA prolyl-aminoacylation that sets the limit of cell viability. Using these suppressors, where prolyl-aminoacylation is decoupled from tRNA methylation, we show that m1G37 neutralizes differential translation of proline codons by the major isoacceptor. Lacking of m1G37 inactivates this neutralization and exposes the need for a minor isoacceptor for cell viability. This work has medical implications for bacterial genomes that exclusively use the major isoacceptor for survival.

microbiology↗

bioRxiv2020

A liquid biopsy platform for detecting gene-gene fusions as glioma diagnostic biomarkers and drug targets

Gliomas account for about 80% of all malignant brain tumours. Diagnosis is achieved by radiographic imaging followed by tumour resection, to determine tumour cell type, grade and molecular characteristics. Glioblastoma multiforme (GBM) is the most common type of glioma, and is uniformly fatal. The median survival of treated GBM patients is 12-15 months. Standard modalities of therapy are unselective and include surgery, radiation therapy and chemotherapy, while precision medicine has yet to demonstrate improvements in disease outcome. We therefore selected GBM as a model to develop a precision medicine methodology for monitoring patients using blood plasma circulating cell-free DNA (cfDNA). Currently, tumour heterogeneity, clonal diversity and mutation acquisition are the major impedances for tailoring personalized therapy in gliomas in general, and particularly in GBM. Thus, a liquid biopsy diagnostics platform based on cfDNA sequencing may improve treatment outcome for GBM patients, by guiding therapy selection. In this study, we processed from 27 patients with glioma, 27 plasma samples for cfDNA isolation and 5 tissue biopsy samples for tumour DNA isolation. From a control group of 14 healthy individuals, 14 plasma samples were processed for cfDNA isolation. In glioma patients, cfDNA concentration was elevated compared to controls. Point mutations found in glioma tissue biopsies were also found in the cfDNA samples (95% identity). Finally, we identified novel chimeric genes (gene-gene fusions) in both tumour and cfDNA samples. These fusions are predicted to alter protein interaction networks, by removing tumour suppressors and adding oncoproteins. Indeed, several of these fusions are potential drug targets, particularly, NTRK or ROS1 fusions, specifically for crizotinib analogues (like entrectinib and larotrectinib) with enhanced penetration of the central nervous system. Taken together, our results demonstrate that novel druggable targets in gliomas can be identified by liquid biopsy using cfDNA in patient plasma. These results open new perspectives and abilities of precision medicine in GBM.

cancer biology↗