Biology subjects

Magni, S.

Publications and source records attributed to Magni, S..

5 recordsLinked to original sources

bioRxiv2026

The glycine-arginine-rich motif of 53BP1 modulates RNA interactions necessary for its liquid-liquid phase separation during DNA Damage Response

The DNA damage response relies on the rapid assembly of repair factors into foci with properties of liquid-liquid phase separation, driven by de novo transcription of damage-induced RNAs. 53BP1 is a key component of these condensates, yet the molecular determinants driving this process remain unknown. Here, through computational, structural and in vitro approaches, we identify the oligomerization domain of 53BP1 and its glycine-arginine-rich (GAR) motif as crucial for RNA interactions and phase separation. Biophysical characterization reveals that 53BP1-RNA condensates can progressively mature into a more stable state, and that GAR mutants display aberrant material properties. Using a cellular model of telomere fusion events, we demonstrate that the GAR motif is essential for 53BP1-mediated DNA repair, which depends on the combined contributions of RNA binding and appropriate condensate biophysical properties. Therefore, RNA-driven 53BP1 condensation is functionally required to maintain genome integrity.

biophysics↗

bioRxiv2022

Dual role of brain endothelial Gpr126 in blood-brain barrier development and ischemic stroke

The blood-brain barrier (BBB) acquires unique properties for regulation of the neuronal function during development. The genesis of the BBB coupled with angiogenesis is orchestrated by the Wnt/{beta}-catenin signaling pathway. Aside from the importance of Wnt/{beta}-catenin signaling, the molecular mechanisms that regulate these processes are poorly understood. Here, we identify the brain endothelial adhesion G-protein-coupled receptor Gpr126 as a novel target gene of Wnt/{beta}-catenin signaling that is required for postnatal BBB development, and its expression is detrimental for ischemic stroke in adults. We show that Gpr126 expression is high in mouse brain endothelium during BBB formation, but decreases in the adult. Inactivation of Gpr126 in postnatal endothelial cells results in vessel enlargement and impairs acquisition of the BBB characteristics, such as increased neurovascular permeability, and reduced basement membrane protein deposition and pericyte coverage. Mechanistically, Gpr126 is required during developmental angiogenesis to promote endothelial cell migration, acting via an interaction between Lrp1 and 3{beta}1-integrin, which couples vessel morphogenesis to BBB formation. Interestingly, in adult mice with an established BBB, the lack of Gpr126 expression in acute ischemic stroke is protective and coupled with reduced microglia activation, which contributes to an improved neurological outcome. These data identify Gpr126 as a promising therapeutic target to treat ischemic stroke.

cell biology↗

bioRxiv2020

Causal dynamical modelling predicts novel regulatory genes of FOXP3 in human regulatory T cells

Regulatory T cells (Tregs), characterized as a CD4+CD25+FOXP3+ subset of T cells, are vital to the induction of immune tolerance and the maintenance of immune homeostasis. While target genes of Treg master regulator FOXP3 have been identified, the upstream regulatory machinery of FOXP3 still remains largely unknown. Here we dynamically model causal relationships among genes from available time-series genome-scale datasets, to predict direct or indirect regulatory genes of FOXP3 in human primary Tregs. From the whole genome, we selected five top ranked candidates for further experimental validation. Following knockdown, three out of the five candidates indeed showed significant effects on the mRNA expression of FOXP3. Further experiments showed that one out of these three predicted candidates, namely nuclear receptor binding factor 2 (NRBF2), also affected FOXP3 protein expression. These results open new doors to identify potential new mechanisms of immune related diseases.

systems biology↗

bioRxiv2019

Single-cell transcriptomics reveals multiple neuronal cell types in human midbrain-specific organoids

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulate in vitro the organisation and function of a respective organ or part of an organ. Human midbrain organoids (hMOs) have been described to contain midbrain-specific dopaminergic neurons that release the neurotransmitter dopamine. However, the human midbrain contains also additional neuronal cell types, which are functionally interacting with each other. Here, we analysed hMOs at high-resolution by means of single-cell RNA-sequencing (scRNA-seq), imaging and electrophysiology to unravel cell heterogeneity. Our findings demonstrate that hMOs show essential neuronal functional properties as spontaneous electrophysiological activity of different neuronal subtypes, including dopaminergic, GABAergic, and glutamatergic neurons. Recapitulating these in vivo features makes hMOs an excellent tool for in vitro disease phenotyping and drug discovery.

neuroscience↗

bioRxiv2016

Dynamical modelling of the heat shock response in Chlamydomonas reinhardtii

Global warming is exposing plants to more frequent heat stress, with consequent crop yield reduction. Organisms exposed to large temperature increases protect themselves typically with a heat shock response (HSR). To study the HSR in photosynthetic organisms we present here a data driven mathematical model describing the dynamics of the HSR in the model organism Chlamydomonas reinhartii. Temperature variations are sensed by the accumulation of unfolded proteins, which activates the synthesis of heat shock proteins (HSP) mediated by the heat shock transcription factor HSF1. Our dynamical model employs a system of ordinary differential equations mostly based on mass-action kinetics to study the time evolution of the involved species. The signalling network is inferred from data in the literature, and the multiple experimental data-sets available are used to calibrate the model, which allows to reproduce their qualitative behaviour. With this model we show the ability of the system to adapt to temperatures higher than usual during heat shocks longer than three hours by shifting to a new steady state. We study how the steady state concentrations depend on the temperature at which the steady state is reached. We systematically investigate how the accumulation of HSPs depends on the combination of temperature and duration of the heat shock. We finally investigate the system response to a smooth variation in temperature simulating a hot day.

plant biology↗