Biology subjects

Paganin, M.

Publications and source records attributed to Paganin, M..

3 recordsLinked to original sources

bioRxiv2025

Translation-specific disruption of Col1a1 expression in multiple models of Spinal Muscular Atrophy can be rescued by Risdiplam.

Spinal muscular atrophy (SMA) is a monogenic neurodegenerative disorder caused by decreased levels of Survival of Motor Neuron (SMN) protein. If left untreated, SMA patients have a poor prognosis, marked by the degeneration of motor neurons, progressive muscle weakness and atrophy. The approval of SMN-restoring therapies that improve symptoms and lifespan in patients with SMA has created emerging, non-neuronal phenotypes and an urgent need for deepening our understanding of disease pathogenesis. Leveraging the knowledge that SMN loss drives alterations in translation, we used multiple tissues from a mouse model of SMA to uncover early translational alterations in key mRNAs and proteins, which act as contributors to pathogenesis and hallmarks of the disease. Among hundreds of differentially translated mRNAs, Col1a1 emerged as a translation-specific manifestation of early defects in the mouse model. These findings were confirmed in fibroblasts derived from patients with varying levels of disease severity. Notably, treatment with SMN-restoring therapies rescued COL1A1 protein levels, particularly in fibroblasts from patients with the most severe forms of the disease. Overall, our study identifies COL1A1 as an indicator of disease severity in SMA, which captures early molecular alterations and respond to SMN-modifying therapies.

molecular biology↗

bioRxiv2022

Filming space-time changes of gene expression with expressyouRcell

The last decade has witnessed massive advancements in high-throughput techniques capable of producing quantifications of transcript and protein levels across time and space, and at high resolution. Yet, the large volume of big data available and the complexity of experimental designs hamper an easy understanding and effective communication of the results. Here we present expressyouRcell, a unique and easy-to-use R package to map the multi-dimensional variations of transcript and protein levels in cell-pictographs. These variations are outcomes of differential and gene set enrichment analysis across space and time. Our tool directly associates these results with up to twenty specific cellular compartments, visualising them as pictographic representations of four different cellular thematic maps. expressyouRcell visually reduces the complexity of displaying gene expression and protein level changes across multiple time-points by generating dynamic representations of cellular pictographs. We applied expressyouRcell to six datasets, demonstrating its flexibility and usability in the visualization of simple and highly effective static and dynamic representations of time course variations in gene expression. Our approach complements classical plot-based methods for visualization and exploitation of biological data, improving the standard quantitative interpretation and communication of relevant results.

bioinformatics↗

bioRxiv2018

USP7 cooperates with NOTCH1 to drive the oncogenic transcriptionalprogram in T cell leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Treatments1-6 show high response rates but have debilitating effects and carry risk of relapse5,7,8. Previous work implicated NOTCH1 and other oncogenes1,2,9-20. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Here, we demonstrate that ubiquitin-specific protease 7 (USP7)21-32 controls leukemia growth by stabilizing the levels of the NOTCH1 and JMJD3 demethylase. USP7 is overexpressed T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 through deubiquitination. USP7 is bound to oncogenic targets and controls gene expression through H2B ubiquitination and H3K27me3 changes via stabilization of NOTCH1 and JMJD3. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and USP7 inhibition alters associated gene activity. These results provide a new model for deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. USP7 inhibition33 significantly blocked T-ALL cell growth in vitro and in vivo. Our studies also show that USP7 is upregulated in the aggressive high-risk cases of T-ALL and suggest that USP7 expression might be a prognostic marker in ALL and its inhibition could be a therapeutic tool against aggressive leukemia.

cancer biology↗