Biology subjects

Manelli, V.

Publications and source records attributed to Manelli, V..

3 recordsLinked to original sources

bioRxiv2024

Context-dependent epigenome rewiring during neuronal differentiation

Transcription factors (TFs) are pivotal in orchestrating lineage decisions and their binding is often accompanied by chromatin remodeling. However, a comprehensive understanding of how cellular and epigenetic contexts influence TF binding and the subsequent activation of lineage-specific programs remains lacking. Here, we dissected the molecular mechanisms underlying the binding of one such TF - Neurog2 and its functional consequences in two cell-types: mouse embryonic stem cells and neural progenitor cells. Our findings reveal that cell-type-specific chromatin accessibility and motif syntax are key determinants for TF binding. While Neurog2 binding primarily leads to chromatin opening, DNA demethylation and increased chromatin interactions, we also uncovered strong indirect, cell-type-specific effects, which ultimately result in vastly different epigenetic landscape. Furthermore, we identify shared and cell-type-specific Neurog2 interactors, including the SWI/SNF and NuRD complexes. Our study shed light on how cellular environment can modulate TF function to establish lineage identity during development.

genomics↗

bioRxiv2019

Glutamine Synthetase-1 induces autophagy-lysosomal degradation of Huntingtin aggregates and ameliorates animal motility in a Drosophila model for HD

Glutamine Synthetase1 (GS1) is an enzyme that catalyzes the ATP-dependent synthesis of L-glutamine from L-glutamate and ammonia as a key element of the glutamate glutamine cycle, a complex physiological process occurring between glia and neurons, necessary to control the homeostasis of glutamate. Using a Drosophila model for Huntingtons disease, we report that expression of GS1 in neurons ameliorates the motility defects of animals expressing the mutant Httex1-Q93 form of the huntingtin gene. At the cellular level, expression of GS1 increases the basal level of autophagy and significantly reduces the size of the toxic Htt-Q93 protein aggregates. In addition, we found that expression of GS1 prevents TOR localization at the lysosomal membrane and reduction in the phosphorylation of its effector S6K. This study reveals a novel function for GS1 in neurons linking its activity to the inhibition of TOR signaling and autophagy. The identification of novel pharmacological regulators of autophagy is of particular interest considering its beneficial role in controlling neuronal health and counteracting the detrimental effects of toxic aggregates of proteinopathies including Huntingtons disease.

cell biology↗

bioRxiv2019

Daedalus and Gasz recruit Armitage to mitochondria, bringing piRNA precursors to the biogenesis machinery

The piRNA pathway is a small RNA-based immune system that silences mobile genetic elements in animal germlines. piRNA biogenesis requires a specialised machinery that converts long single-stranded precursors into small RNAs of ~25-nucleotides in length. This process involves factors that operate in two different subcellular compartments: the nuage/Yb-body and mitochondria. How these two sites communicate to achieve accurate substrate selection and efficient processing remains unclear. Here, we investigate a previously uncharacterized piRNA biogenesis factor, Daedalus (Daed), that is located on the outer mitochondrial membrane. Daed is essential for Zucchini-mediated piRNA production and for the correct localisation of the indispensable piRNA biogenesis factor, Armitage (Armi). We find that Gasz and Daed interact with each other and likely provide a mitochondrial \"anchoring platform\" to ensure that Armi is held in place, proximal to Zucchini, during piRNA processing. Our data suggest that Armi initially identifies piRNA precursors in nuage/Yb-bodies in a manner that depends upon Piwi and then moves to mitochondria to present precursors to the mitochondrial biogenesis machinery. These results represent a significant step in understanding a critical aspect of transposon silencing, namely how RNAs are chosen to instruct the piRNA machinery in the nature of its silencing targets.

molecular biology↗