Biology subjects

Santoro, J.

Publications and source records attributed to Santoro, J..

3 recordsLinked to original sources

bioRxiv2026

DNMT1-Mediated Epigenetic Reprogramming Drives KMT2A Amplifications and Rearrangements

MLL/KMT2A amplifications and rearrangements are prevalent in infant, adult, and therapy-induced leukemia; however, the molecular contributors controlling these alterations remain elusive. Here, we reveal that rapid CTCF degradation generates local genome structure alterations at KMT2A and copy gains and rearrangements. We then established a conserved, coordinated interplay between DNA and histone methylation pathways that control CTCF occupancy, and in turn, KMT2A locus stability. For example, DNMT1 overexpression promotes increased H3K9 methylation, reduced CTCF occupancy, and causes KMT2A alterations. However, DNMT1 inhibition suppresses these events and KMT2A alterations caused by topoisomerase II inhibition. Locus-specific epigenome targeting demonstrated that DNA or H3K9 methylation promotes KMT2A copy gains and rearrangement, whereas targeted TET activity suppresses these events upon methylation perturbation or doxorubicin treatment. These findings identify a conserved, coordinated DNA-histone methylation axis governing KMT2A amplifications and rearrangement susceptibility, revealing biomarkers and therapeutic targets to predict and intercept these events in cancer.

cancer biology↗

bioRxiv2023

Neuregulin-1 protects against respiratory viral induced mortality

Respiratory viral infections due to RNA viruses such as respiratory syncytial virus (RSV) and influenza lead to significant morbidity and mortality. Using a natural rodent pathogen similar to RSV, Sendai virus (SeV), we found that mice made atopic with house dust mite before viral infection all survived a normally lethal SeV infection. Moreover, adoptive transfer of CD11c+ cells from atopic mice delayed viral mortality. Neuregulin-1 (NRG1) message was highly expressed in CD11c+ cells from atopic mice and atopic lungs and bronchoalveolar lavage fluid had elevated levels of NRG1 protein. Administration of NRG1 protected non-atopic mice from death and associated with reduced alveolar epithelium permeability. Utilizing an in vitro system of well-differentiated human bronchial epithelial cells and mouse tracheal epithelial cells NRG1 reduced RSV and SeV titers. Expression of genes that play a role in airway epithelium integrity and stability were altered by NRG1; potentially regulating viral induced dysregulation of the epithelia and suggesting NRG1 mediated maintenance of homeostasis. In conclusion, our studies demonstrate atopy induced NRG1 likely plays a novel role in survival from severe respiratory viral infections and may have therapeutic value to prevent mortality from these infections. SignificanceSevere respiratory viral infections are associated with significant mortality in infants and the elderly; however, allergic disease can protect from these outcomes. This study identified a protein called neuregulin-1 (NRG1), produced by cells of the immune system in allergic mice, that provides a survival advantage against respiratory viral infection. NRG1 pretreatment in non-atopic mice infected with a lethal dose of a rodent RNA virus (Sendai virus), similar to human respiratory syncytial virus, significantly reduced death. Further, NRG1 pretreatment reduced viral replication in human and mouse airway epithelial cell cultures. These studies signify a potential therapeutic role of NRG1 in modulating the severity of respiratory viral infections.

immunology↗

bioRxiv2020

Optimisation and comparison of orthogonal methods for separation and characterisation of extracellular vesicles to investigate how representative infant milk formula is of milk

This study aimed to separate and characterise extracellular vesicles (EV) from infant milk formula (IMF) and skim milk (SM), to determine how representative the EV content of IMF is to SM. Contaminant casein micelles, due to their abundance and overlapping size, were removed followed by either differential ultracentrifugation (DUC) or gradient ultracentrifugation (GUC). Characterisation included BCA, SDS-PAGE, nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), immunoblotting, and imaging flow cytometry (IFCM). NTA reported significantly reduced concentrations of EVs/particles in IMF versus SM; TEM showed intact SM-derived EVs to sparse and disrupted EV-like structures in IMF. Compared to IMF, noticeably stronger bands for EV biomarkers were observed by immunoblotting in SM, indicating compromised EV proteins in IMF; also supported by IFCM. Altogether, we established that EVs are substantially compromised during IMF processing. Furthermore, an optimised method combining acid pre-treatment and GUC for EV separation from milk products has been established.

molecular biology↗