Biology subjects

Dubnov, S.

Publications and source records attributed to Dubnov, S..

7 recordsLinked to original sources

bioRxiv2025

The Quest for a Universal Parkinson's Transcriptomics Signature is Derailed by Inherent Variability between Patients

ObjectiveTo systematically evaluate the reproducibility and clinical utility of published blood mRNA-based gene signatures for classifying PD from healthy controls, and to uncover the pitfalls that limit their performances. MethodsWe validated the classification performance of 13 gene signatures unique for PD (published 2015-2025) using the Parkinsons Progression Markers Initiative (PPMI) database. We further validated classification performance on data collected in a prospective clinical trial where demographic and clinical parameters were minimized and environmental confounders were strictly controlled. Sources of gene expression variability were studied by mean pairwise distance analysis. ResultsGene overlap between signatures was low (11/411, 2.7%) but statistically significant (P<0.001) and enriched with genes involved in lipid metabolism. The majority (10/13) of these signatures retained statistical significance when tested on the PPMI dataset, but their classification performance was modest (median AUC 59.7%), substantially lower than originally reported. Classification performance improved when comparing GBA1-associated PD to controls (median AUC 65.4%, P=0.006). A prospective trial (16 PD patients, 14 controls) with rigorous environmental standardization did not improve classification accuracy. Inter-individual expression variability is the dominant limiting factor in classifier performance. Variability was not impacted by long-term levodopa therapy. InterpretationWhile blood transcriptomic signatures unique to PD are reproducible and may elucidate PD pathophysiology, their broad clinical utility remains severely limited by inherent inter-individual variability. Future research should prioritize biomarkers of divergence rather than the pursuit of a universal PD signature.

bioinformatics↗

bioRxiv2025

Spatiotemporal dynamics of tumor microenvironment remodelling

During tumorigenesis, interactions between tumor and stromal cells progressively remodel the tumor microenvironment (TME) towards pro-tumoral functions. Understanding early TME remodeling dynamics is therefore crucial for developing interceptive therapies. However, clinical samples typically provide isolated, late tumorigenesis snapshots. To overcome this limitation, we generated triple-negative breast cancer mice that develop multifocal, asynchronous tumors along a continuous luminal-to-basal transdifferentiation trajectory. Ordering spatial transcriptomes from 100+ ducts along this trajectory reveals the spatiotemporal dynamics of TME remodeling and underlying molecular mechanisms. Cancer-associated myofibroblasts (myCAFs) emerge as key players in advanced tumors, where they orchestrate pro-invasive remodeling of the tumor-stromal interface. myCAFs are conserved in patient-derived xenograft models and steer tumor trajectories towards invasive phenotypes when co-injected with tumor cells in syngeneic mice. Our study shows that temporal ordering of spatially-resolved disease snapshots unravels some of the molecular "forces" that, starting from the cell-of-origin, propel cells/microenvironments along a disease trajectory.

cancer biology↗

bioRxiv2024

Identifying maximally informative signal-aware representations of single-cell data using the Information Bottleneck

Rapid advancements in single-cell RNA-sequencing (scRNA-seq) technologies revealed the richness of myriad attributes encompassing cell identity. However, the complexity of the data hinders tasks focusing on a specific biological signal. To address this challenge, we introduce bioIB, a framework based on the Information Bottleneck method, designed to extract an interpretable compressed representation of scRNA-seq data, optimally-informative with respect to a desired biological signal, such as developmental stage or disease state. Provided with cellular labels representing the signal of interest, bioIB generates weighted gene clusters, termed metagenes, that compress the data, while maximizing signal-specific information. Following the Information Bottleneck principle, bioIB identifies an optimal trade-off between data compression and retaining target information. Further, bioIB provides the hierarchical structure of the metagenes, revealing the interconnections between the corresponding biological processes and cellular populations, such as the developmental hierarchy of hematopoietic cell types. We showcase bioIBs applicability to diverse biological contexts, including Alzheimers Disease, epithelial-to-mesenchymal transition, immune development and hematopoiesis, demonstrating that the compressed representations capture signal-associated molecular pathways and expose cellular subpopulations with prominent phenotypes such as transition states and disease association.

bioinformatics↗

bioRxiv2023

Knockout of the longevity gene Klotho perturbs aging- and Alzheimer's disease-linked brain microRNAs and tRNA fragments

Introductory paragraphOverexpression of the longevity gene Klotho prolongs, while its knockout shortens lifespan and impairs cognition via altered fibroblast growth factor signaling that perturbs myelination and synapse formation; however, comprehensive analysis of Klothos knockout consequences on mammalian brain transcriptomics is lacking. Here, we report the altered levels under Klotho knockout of 1059 long RNAs, 27 microRNAs (miRs) and 6 tRNA fragments (tRFs), reflecting effects upon aging and cognition. Perturbed transcripts included key neuronal and glial pathway regulators that are notably changed in murine models of aging and Alzheimers Disease (AD) and in corresponding human post-mortem brain tissue. To seek cell type distributions of the affected short RNAs, we isolated and FACS-sorted neurons and microglia from live human brain tissue, yielding detailed cell type-specific short RNA-seq datasets. Together, our findings revealed multiple Klotho deficiency-perturbed aging- and neurodegeneration-related long and short RNA transcripts in both neurons and glia from murine and human brain.

neuroscience↗

bioRxiv2023

Lysine tRNA fragments and miR-194-5p co-regulate hepatic steatosis via beta-Klotho and Perilipin 2

Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct and cooperative NAFLD roles of LysTTT-5tRF transfer RNA fragments and microRNA miR-194-5p. Unlike lean animals, dietary-induced NAFLD mice showed hepatic co-declined LysTTT-5tRF and miR-194-5p levels, restored following hepatic steatosis-suppressing miR-132 antisense oligonucleotide treatment. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5tRF levels while increasing lipid accumulation. Importantly, transfecting fattened cells with a synthetic LysTTT-5tRF mimic elevated the metabolic regulator {beta}-Klotho mRNA levels while declining triglyceride amounts by 30% within 24 hours. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug repurposing compounds, Danazol and Latanoprost elevated miR-194-5p or LysTTT-5tRF levels. The different yet complementary roles of miR-194-5p and LysTTT-5tRF offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.

molecular biology↗

bioRxiv2023

Ribosomal protein L24 modulates mammalian microRNA processing and transfer RNA fragment production

The evolutionary mechanism(s) underlying the expression of novel microRNAs (miRs) are still elusive. To explore this issue, we studied the expression of intronic primate-specific hsa-miR-608, located in the Semaphorin 4G (SEMA4G) gene. Engineered humanized mice carrying human miR-608 flanked by 250 bp in the murine Sema4g gene expressed miR-608 in several tissues. Moreover, miR-608 flanked by shortened fragments of its human genome region elevated miR-608 levels by 100-fold in murine and human-originated cells, identifying the 150 nucleotides 5 to pre-miR-608 as an active promoter. Surprisingly, pulldown of this 5 sequence revealed tight interaction with ribosomal protein L24 (RPL24), which inhibited miR-608 expression. Furthermore, RPL24 depletion altered the levels of 22 miRs, and we discovered that direct interaction of RPL24 with DDX5, a component of the large microprocessor complex, inhibits pri-miR processing. Moreover, RPL24 depletion resulted in Angiogenin (ANG)-mediated production of 5-half tRFs in human cells, and altered plant tRF profiles. Expanding previous reports that RPL24 regulates miR processing in Arabidopsis thaliana, we implicate RPL24 in an evolutionarily-conserved regulation of miR processing and tRF production. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/539194v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@4f2058org.highwire.dtl.DTLVardef@d4a2cdorg.highwire.dtl.DTLVardef@c7786org.highwire.dtl.DTLVardef@7b1608_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease

IntroductionFemales with Alzheimers disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in tRNA fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). MethodsWe analyzed small RNA-sequencing data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. ResultsNAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. DiscussionOur findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

bioinformatics↗