Biology subjects

Bagnetto, C.

Publications and source records attributed to Bagnetto, C..

3 recordsLinked to original sources

bioRxiv2026

SAGA/ATAC complexes sustain aberrant chromatin regulation and promote tumorigenesis in diffuse midline glioma

Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors characterized by chromatin and transcriptional dysregulation induced by H3K27M mutations, with a median survival of 11-15 months. We identified multiple components of the SAGA and ATAC chromatin regulatory complexes as DMG genetic dependencies and found that genetic or pharmacological inhibition of the SAGA/ATAC-associated chromatin reader SGF29 reduces DMG proliferation in vitro and prolongs survival in xenograft models. Small molecule inhibitors targeting SAGA/ATAC-associated histone acetylation, ubiquitination, and methylation similarly suppress DMG growth. Integrative chromatin and transcriptomic profiling reveals that disruption of SAGA/ATAC through SGF29 knockout remodels the DMG chromatin landscape, producing distinct alterations at metabolic genes (loss of H3K9ac) and at embryonic/neurodevelopmental genes (redistribution of H3K4me3 and H3K27me3) and accompanying transcriptional changes. We further show that inhibition of the SAGA/ATAC-associated KAT2A/2B histone acetyltransferases represses cholesterol metabolism gene expression and that combined KAT2A/2B and cholesterol synthesis inhibition synergistically suppresses DMG growth in vitro and in a xenograft model. Together, these findings establish a mechanistic link between SAGA/ATAC-dependent chromatin regulation and the transcriptional and metabolic dysregulation underlying DMG malignancy. SignificanceWe demonstrate that SAGA/ATAC-dependent chromatin regulation sustains malignant transcription controlling cholesterol metabolism, proliferation, and cell fate in DMG, suggesting that a SAGA/ATAC-regulated epigenome-metabolome axis may be targeted to treat DMG.

cancer biology↗

bioRxiv2025

Ankyrins are essential for synaptic integrity of photoreceptors in the mouse outer retina

Retinal circuit assembly relies on the precise timing and positioning of key molecules between neuronal partners to mediate proper synapse formation. In the outer retina, horizontal cells are important interneurons that make the first contacts to photoreceptors and begin to segregate visual information into two distinct pathways by selectively forming synapses to the different types of photoreceptors. Dendrites of horizontal cells synapse exclusively to cone photoreceptors whereas the axon terminal synapses to rod photoreceptors. Failure to properly form these early connections disrupts the downstream connectivity of other postsynaptic neurons and leads to abnormal visual function. Although these early events are critical for proper synapse development, little is known about the molecular mechanisms that establish horizontal cell to photoreceptor connectivity during development. In the present study, we performed single-cell RNA sequencing and uncovered new molecules that are highly expressed in horizontal cells. These include different members of the cytoskeletal scaffolding family of Ankyrins that are known to form specialized regions within neurons by recruiting different molecules to the membrane and linking them to the cytoskeleton. Specifically, we found Ankyrin-B to be highly expressed in horizontal cells at early time points and Ankyrin-G to be expressed at later stages. Loss of both Ankyrin-B and Ankyrin-G leads to synaptic defects between horizontal cells and photoreceptors and disrupts in vivo retinal responses. In summary, our findings uncovered a new role for Ankyrins in mediating synaptic connectivity between horizontal cells and photoreceptors required for normal visual function. SIGNIFICANCE STATEMENTIn the mammalian retina, the first synapse between photoreceptors and their downstream targets begins to separate visual information into two distinct pathways. During retinal development, photoreceptors first make contacts to horizontal cells in a temporal- and spatial-specific manner. Although this initial contact is critical for synaptogenesis, little is known about the key molecules responsible for selective wiring of horizontal cells to photoreceptors. In this study, we performed single-cell RNA sequencing and identified the family of cytoskeletal scaffolding proteins Ankyrins to be differentially expressed in horizontal cells. Loss of Ankyrins impairs synaptic connectivity between horizontal cells and their photoreceptor partners leading to abnormal visual responses. Taken together, our work uncovered a new function of Ankyrins at photoreceptor synapses.

neuroscience↗

bioRxiv2022

bII-spectrin is required for synaptic positioning during retinal development

Neural circuit assembly is a multi-step process where synaptic partners are often born at distinct developmental stages, and yet they must find each other and form precise synaptic connections with one another. This developmental process often relies on late-born neurons extending their processes to the appropriate layer to find and make synaptic connections to their early-born targets. The molecular mechanism responsible for the integration of late-born neurons into an emerging neural circuit remains unclear. Here we uncovered a new role for the cytoskeletal protein {beta}II-spectrin in properly positioning pre- and post-synaptic neurons to the developing synaptic layer. Loss of {beta}II-spectrin disrupts retinal lamination, leads to synaptic connectivity defects, and results in impaired visual function. Together, these findings highlight a new function of {beta}II-spectrin in assembling neural circuits in the mouse outer retina. HighlightsO_LIEstablished a new role for {beta}II-spectrin in assembling retinal circuits C_LIO_LI{beta}II-spectrin positions pre- and post-synaptic neurons to the developing synaptic layer C_LIO_LIEarly positioning of processes to the OPL is required for synaptogenesis C_LIO_LILoss of {beta}II-spectrin disrupts synaptic connectivity and impairs visual function C_LI

neuroscience↗