Biology subjects

Kwon, W.

Publications and source records attributed to Kwon, W..

3 recordsLinked to original sources

bioRxiv2025

Mutant IDH impairs chromatin binding by PDGFB to promote chromosome instability

Non-canonical roles for growth factors in the nucleus have been previously described, but their mechanism of action and biological roles remain enigmatic. Platelet-derived growth factor B (PDGFB) can drive formation of low-grade glioma and here we show that it localizes to the nucleus of human glioma cells where it binds chromatin to preserve genome stability and cell lineage. Failure of PDGFB to localize to the nucleus leads to chromosomal abnormalities, aberrant heterochromatin architecture and accelerated tumorigenesis. Furthermore, nuclear localization of PDGFB is reliant upon the expression levels and mutation status of isocitrate dehydrogenase (IDH). Unexpectedly, we identified macrophages as the predominant source of PDGFB in human, finding that immune-derived PDGFB can localize to the nucleus of glioma cells. Collectively, these studies show that immune derived PDGFB enters the nucleus of glioma cells to maintain genomic stability, while identifying a new mechanism by which IDH mutations promote gliomagenesis.

cancer biology↗

bioRxiv2023

Activity-dependent induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

Neuronal activity drives global alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. Here we show that neuronal activity induces widespread transcriptional upregulation and downregulation in astrocytes, highlighted by the identification of a neuromodulator transporter Slc22a3 as an activity-inducible astrocyte gene regulating sensory processing in the olfactory bulb. Loss of astrocytic Slc22a3 reduces serotonin levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduces expression of GABA biosynthetic genes and GABA release, culminating in olfactory deficits. Our study reveals that neuronal activity orchestrates transcriptional and epigenomic responses in astrocytes, while illustrating new mechanisms for how astrocytes process neuromodulatory input to gate neurotransmitter release for sensory processing.

neuroscience↗

bioRxiv2020

Ventral hippocampal mossy cell hyperactivity degrades dorsal hippocampal mnemonic function via longitudinal projections

BackgroundThe anterior hippocampus of individuals with early psychosis or schizophrenia is hyperactive, as is the ventral hippocampus in rodent models for schizophrenia risk. Hyperactive ventral hippocampal projections to extrahippocampal brain regions contribute to schizophrenia symptoms, but less is known about the functional effects of hyperactive projections within the hippocampal formation long axis. We approached this question by testing whether hyperactivation of ventral dentate gyrus (DG) mossy cells (MCs), which densely project intrahippocampally to the dorsal DG, influences spatial memory, a cognition dependent on intact dorsal DG function. MethodsIn CD-1 mice, we targeted dorsal DG-projecting ventral DG MCs using an adeno-associated virus intersectional strategy. In vivo fiber photometry recording of ventral DG MCs was performed during exploratory behaviors. We targeted excitatory chemogenetic constructs to ventral DG MCs and tested whether their hyperactivation impaired encoding in a spatial memory task. ResultsVentral DG MCs were activated during behavior related to environmental information gathering (rearing) but not during non-exploratory motor behaviors. Ventral DG MCs made functional monosynaptic inputs to dorsal DG granule cells, with chemogenetic activation of ventral DG MCs leading to increased activity of dorsal DG granule cells. Finally, chemogenetic activation of ventral DG MCs during the encoding phase of an object location memory task impaired retrieval 24 hours later, without effects on locomotion or other exploratory behaviors. ConclusionsThese data suggest that localized hippocampal hyperactivity may have longitudinal intrahippocampal functional consequences, supporting study of longitudinal circuits as targets to mitigate cognitive deficits associated with schizophrenia.

neuroscience↗