Biology subjects

Chu, J.

Publications and source records attributed to Chu, J..

At least 19 recordsLinked to original sources

bioRxiv2026

N-Acetylglucosamine ameliorates knee osteoarthritis by enhancing UDP-GlcNAc conversion and chondrocyte DNA repair capacity

Background: Knee osteoarthritis (KOA) is a degenerative joint disease characterized by progressive cartilage degradation and synovial inflammation, while current therapies offer only symptomatic relief. This study aimed to determine whether N-acetylglucosamine (GlcNAc) is superior to glucosamine hydrochloride (GlcN{middle dot}HCl) in slowing the progression of KOA and to elucidate the underlying mechanisms involved. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed to assess serum concentrations of UDP-GlcNAc to conduct a comprehensive evaluation of the pharmacokinetics and pharmacodynamics associated with both GlcNAc and GlcN{middle dot}HCl. Using a destabilization of the medial meniscus (DMM) rat model, we performed micro-computed tomography and histopathological assessments to evaluate structural changes in the joint tissues. Additionally, we conducted bulk RNA sequencing, flow cytometry and ELISA to validate the efficacy of GlcNAc in anti-inflammatory immunoregulation and DNA repair in knee cartilage. Results: GlcNAc achieved higher peak serum concentrations and more efficient conversion to UDP-GlcNAc than GlcN{middle dot}HCl, with UDP-GlcNAc levels 4.57 times higher at 9 hours after administration. GlcNAc significantly attenuated KOA-like pathological changes, downregulated catabolic markers Mmp3 and Adamts4, decreased pain-related neural markers Pgp9.5 and Ngf, and alleviated pain sensitivity. RNA-seq identified 4,395 downregulated DEGs in DMM rats, of which GlcNAc upregulated 2,808 compared to only 391 by GlcN{middle dot}HCl. GlcNAc promoted DNA repair and adaptive immune cell differentiation pathways, and decreased serum IL-1{beta}, IL-6, and IL-17. Four candidate DNA repair genes, Hist1h2an, Poli, Ube2t, and Hells, were identified as significantly upregulated by GlcNAc, with GSEA confirming homologous recombination repair pathway enrichment. Conclusion: This study shows GlcNAc outperforms GlcN{middle dot}HCl in rat DMM knee osteoarthritis via multiple mechanisms, including 4.57-fold higher UDP-GlcNAc conversion, reduced cartilage degeneration, immune rebalancing, and DNA repair activation, supporting GlcNAc as a promising KOA candidate warranting further clinical study.

pharmacology and toxicology↗

bioRxiv2026

Spatial and Molecular Progression of Neural Progenitor Cells in the Developing Human Dentate Gyrus

The large diversity of neuronal and glial cell types in the human brain is underpinned by foundational cell populations known as neural progenitor cells (NPCs). The dentate gyrus (DG) of the hippocampus, a key structure in learning and memory, maintains a tightly organized NPC population into adulthood across many mammalian species. However, the emergence, organization and persistence of NPCs in the human hippocampus remain poorly characterized. Reports of NPCs in the juvenile, adult, and aged periods have been variable, reflecting differences in identification criteria and highlighting the need for a unified framework across development. In this study, we provide a spatial and molecular map of the developmental trajectory of NPCs in the human DG, combining multimodal transcriptomic analysis within a neuroanatomical context. At mid-gestation, we observed changes in the structural and cellular arrangement of the hippocampus, coinciding with the emergence of a multicellular NPC layer within the DG, herein named the granular-hilar progenitor zone (GHPZ). Neurogenic transcriptomic signatures in the GHPZ were diminished by early infancy, coinciding with a reduction in NPC number as they progressed toward an astrocytic program. At childhood, the GHPZ dissolved with only sparse radial NPCs remaining in the DG. Lastly, we validated WNT signaling pathway-associated genes as NPC identity markers in the developing human DG, observing a decline in their expression after infancy. Our study defines the steep decline of NPCs from gestation to the postnatal period, identifies their progression to an astrocytic nature, and sets the molecular blueprint for NPC identification in the human DG. HighlightsO_LIMultimodal mapping of neural progenitor cells from gestational to postnatal stages in the human hippocampus C_LIO_LIFormation of the granular-hilar progenitor zone within the dentate gyrus at mid-gestation C_LIO_LINeurogenic potential declines sharply from the prenatal period to childhood, with radial glia cells progressively acquiring astrocytic features C_LIO_LIDevelopmental modulation of the WNT signaling pathway accompanies radial glia cell transitions C_LI

neuroscience↗

bioRxiv2026

DeSCENT: Deconvolutional Single-Cell RNA-seq Enhances Transcriptome-based Cancer Survival Analysis

MotivationAccurate cancer survival prediction requires modeling tumor heterogeneity across both population and cell levels. Most cancer survival analyses use tumor transcriptomes only, since cohorts are usually measured with bulk RNA-seq but are rarely recorded with single-cell RNA-seq. This prevents the direct use of cell-level transcriptomes in cancer survival analysis. ResultsTo bridge this gap, we propose using bulk RNA-seq deconvolution algorithms to reconstruct each subjects scRNA-seq profile from their bulk data. Then, by combining both scRNA-seq and bulk RNA-seq together with their survival labels (paired to bulk), we perform multimodal transcriptome-based survival analysis. We built this framework as DeSCENT and evaluated it with common survival models on eight TCGA cancer cohorts. Results showed notable and consistent improvements in C-index over bulk-only models or models using cellular information alone. AvailabilityOur code is available at GitHub: https://github.com/YonghaoZhao722/DeSCENT. Contactzpluo@swjtu.edu.cn; y.he@imperial.ac.uk Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2026

Mitotic bookmarking by Prox1 preserves mammalian neuronal lineage identity memory via promoting timely H3K27me3 restoration

Mitosis poses a daunting challenge to transgenerational inheritance of cell identity memory. How neuronal lineage identity is faithfully transmitted across mitosis remains largely unexplored. Here we report that, in mouse hippocampus, the transcription factor Prox1 acts as a mitotic bookmark for safeguarding neuronal lineage identity across cell divisions. Prox1 exhibits mitotic retention in dentate gyrus (DG) neural stem cells and defines DG lineage identity by suppressing the alternative cornu ammonis (CA) identity. Mitotic bookmarking by Prox1 at key bivalent CA identity genes promotes timely and precise restoration of Polycomb repressive complex 2 (PRC2)-mediated H3K27me3 deposition to avoid ectopic expression of CA identity genes and lineage identity crisis. Remarkably, specific mitotic retention-deficient Prox1 conditional knock-in mice produce severe DG developmental defects. Thus, mitotic bookmarking imprints neuronal lineage identity in mouse hippocampus, which is likely to represent a fundamental principle underlying the preservation of lineage identity memory in mammalian brain development.

developmental biology↗

bioRxiv2026

GM-CSF regulates ILC states and myeloid cell signaling during ulceration in Crohns disease

Macrophage (M-), granulocyte (G-), and granulocyte-macrophage (GM-) colony-stimulating factors (CSFs) regulate myeloid cell function, yet their relative roles during inflammation remain poorly defined. To uncover how CSFs shape spatial immune niches in Crohns disease, we performed Xenium single-cell spatial transcriptomics on ileal tissues, revealing cell-type-specific expression and source-target interactions for each CSF. GM-CSF, unlike M-CSF or G-CSF, was locally enriched in ulcerated regions where lymphocytes adjacent to macrophage aggregates signaled through STAT5 phosphorylation. To study functional consequences, we developed a csf2rb-/- zebrafish model of intestinal injury. Using this model, we found that loss of GM-CSF signaling exacerbated epithelial damage and inflammation, whereas recombinant human GM-CSF limited injury by restraining ILC1 expansion, sustaining ILC3 maintenance, and promoting IL-22 production. Cross-species single-cell analysis revealed conserved ILC gene modules and GM-CSF-dependent transcriptional networks linking lymphoid and myeloid populations. These findings establish GM-CSF as a critical spatial regulator of myeloid- lymphoid crosstalk and intestinal immune homeostasis in Crohns disease.

immunology↗

bioRxiv2025

METTL3-mediated SOCS3 m6A Modification in Preserving CD4+ T Cell Homeostasis in HIV Infected Long-term Non-progressors

The maintenance of normal CD4+ T cell levels in human immunodeficiency virus (HIV) infected long-term non-progressors (LTNPs) remains elusive. N6-methyladenosine (m6A) regulates RNA metabolism and immune function, but its role in LTNP pathogenesis is unelucidated. This study integrated in vivo analyses of peripheral blood mononuclear cells (PBMCs) from LTNPs, typical progressors (TPs), ART-treated patients, and healthy controls with in vitro experiments using the MT2-HIV-1B model to explored the m6A regulatory role in LTNPs. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) identified uniquely elevated m6A modification abundance and METTL3 expression in LTNPs vs. TPs. Differential m6A and mRNA analysis bighlighted enrichment of innate immunity/inflammation pathways, particularly the SOCS/IL/JAK axis. Further experiments confirmed that METTL3 mediates m6A modification of SOCS3, which suppresses JAK2/STAT4 phosphorylation to modulate IL-12/IFN-{gamma}/IL-4 expression. These findings uncover a novel m6A-METTL3-SOCS3 regulatory axis underlying HIV long-term non-progression, explaining preserved CD4+ T cell homeostasis in LTNPs. IMPOTANCE LTNPs represent a unique subset of HIV-infected individuals who naturally maintain normal CD4 T cell levels and slow disease progression, offering a valuable model to dissect host protective mechanisms against HIV. mA modification has emerged as a pivotal regulator roles in HIV replication and T cell activation, yet its contribution to LTNP biology has remained unclear. This novel mechanism provides a potential explanation for the maintenance of normal CD4+ T cell levels in LTNPs. Our findings shed light on the molecular basis of HIV-1 long-term non-progression and offered crucial insights for developing functional cure for AIDS and new host immune strategies.

immunology↗

bioRxiv2025

Quantitative Substrate Kinetics Screening: One-Pot LC/MS Based Approach to Map Protease Specificity

Proteases play critical roles in many biological processes and diseases. Proteases tend to have limited and overlapping specificities, which hinders our understanding of their roles in physiology. We designed a naive protease substrate library with the aim of fully utilizing modern mass spectrometry proteomics tools to quantitatively map protease substrate specificity. A library of approximately 200,000 peptides was efficiently produced in E. coli with sufficient library diversity to identify cleavage efficiency of thousands of substrates for most proteases in a single assay. Each experiment results in ample substrate kinetics data to build a positional specificity matrix that quantitatively maps protease specificity. We apply this method to two different proteases, GluC commonly used as a proteomics tool, and Fibroblast Activation Protein Alpha that is overexpressed in activated fibroblasts of epithelial cancers and fibrotic diseases. This research quantitatively maps substrate specificity for GluC and FAP in a single assay and can be applied to map substrate specificity for most proteases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=122 HEIGHT=200 SRC="FIGDIR/small/680748v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1496d11org.highwire.dtl.DTLVardef@1979fc1org.highwire.dtl.DTLVardef@17967e8org.highwire.dtl.DTLVardef@194b741_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Longitudinal analysis of bacterial community dynamics in normal hospital ward following patient occupancy

The hospital microbiome significantly influences patient recovery and clinical outcomes. However, the dynamics of microbial colonization and transmission following initial patient occupancy remain poorly understood. Here, we employed 16S rRNA gene amplicon sequencing to investigate bacterial community dynamics on surfaces within neurosurgery ward and patients as a new hospital became operational. Our results showed that bacterial colonization in hospital wards follows distinct site-specific patterns, after hospital opening, alpha diversity was significantly increased on floors and drawer handles but decreased on bedrails and faucet handles compared to preopening. Beta diversity analysis showed that surfaces frequently contacted by patients exhibited the greatest compositional turnover, such as bedrails, drawer handles, and faucet handles, bacterial communities in after-opening were more homogeneous across sites than preopening, indicating potential bacterial transmission. Moreover, we found following patient admission, patient hand-derived microbiomes exert a significant influence on the bacterial communities in hospital wards, with a particularly pronounced impact on bedrails. Additionally, the potential disease risk of bedrails in post-opening was significantly higher than preopening. Taken together, these findings underscore the critical role of human contact in shaping hospital microbiomes and highlight the importance of targeted infection control strategies to mitigate pathogen transmission.

bioinformatics↗

bioRxiv2025

Cerebral Organoids Uncover Mechanisms of Neural Activity Changes in Epileptogenesis

Neurological disorders often originate from progressive brain network dysfunctions that start years before symptoms appear. How these changes emerge in the developing human brain remains elusive due to a lack of tractable model systems. Here, we show a cerebral organoid model of Tuberous Sclerosis Complex (TSC) that recapitulates hallmarks of epileptogenesis in vitro. We compare extracellular recordings of TSC organoids with intraoperative electrocorticography from TSC patients to reveal striking functional similarities, including high-frequency oscillations - an electrical biomarker for epileptogenic tissue. In TSC, a human-specific interneuron sub-type derived from the caudal ganglionic eminence drives network hyper-synchronization through increased spontaneous firing and altered excitability. Inhibiting overproliferation of its progenitors via long-term epidermal growth factor receptor inhibition prevented the onset of this pathological phenotype at functional and morphological levels. Our work shows that organoids allow mechanistic analysis of emerging neural network phenotypes, enabling anti-epileptogenic drug testing in a human brain development model.

neuroscience↗

bioRxiv2025

Cell Type-Specific Changes in Dendritic Spines Across Adolescence Within Mouse Medial Prefrontal Cortex

Across species, cognitive capacities that rely on the frontal cortex do not fully mature until adulthood. Adolescent circuit refinement, including structural remodeling of dendritic spines, is believed to underlie this protracted maturation. Understanding cell type-dependent patterns of structural maturation would provide important insight into frontal cortex development. Here, we leveraged retrograde adeno-associated viruses to quantify dendritic spines on pyramidal tract (PT) vs. intratelencephalic (IT) neuronal populations in parallel within the mouse medial prefrontal cortex (mPFC) across adolescence. IT-type neurons showed opposing changes in mushroom and thin spines that were: 1) consistent with increasing synaptic maturity and 2) largely absent in PT-type neurons. We next probed the function of brain-resident immune cells, microglia, by transiently ablating them within the mPFC at mid-adolescence. This led to cell type-dependent changes in dendritic spines in late adolescence, with thin spine proportion increasing on both cell types but total spine density increasing on IT-type neurons only. Meanwhile, there was no effect on performance in an mPFC-dependent task of cognitive flexibility at either late adolescent or adult time points following microglia ablation. These findings provide evidence that mPFC IT-type neurons undergo greater spine remodeling during adolescence compared to PT-type neurons and implicate microglia as potential mediators.

neuroscience↗

bioRxiv2025

Macrophage-like vascular smooth muscle cells dominate early atherosclerosis and are inhibited by targeting iron regulation

Vascular smooth muscle cells (VSMCs) contribute dynamically to atherosclerosis at all stages but the molecular drivers of their phenotypic switching, especially during early plaque development, and how they contribute to plaque progression remain unclear. We performed spatial transcriptomics on 12 human aortic tissues with and without atherosclerotic plaque. Macrophage-like SMCs were the predominant cell-type in the atheroma, displaying high iron storage and dysregulation, confirmed by spatial elemental mapping with nuclear microscopy. The combination of soluble iron and oxidized LDL promoted foamy macrophage-like VSMC cell state transition, while chelation inhibited this switching. In vivo, iron dysregulation induced neointimal thickening and macrophage-like switching in wire-injured Ldlr-/- mice, which was significantly reversed by ferrostatin-1, a ferroptosis inhibitor. These data show how targeting iron regulation modifies the macrophage-like VSMC cell state, and inhibits disease progression in atherogenesis.

genomics↗

bioRxiv2025

In silico drug sensitivity predicts subgroup-specific therapeutics in medulloblastoma patients

BackgroundMedulloblastoma is the most common malignant pediatric brain tumor. Survival rates vary widely between subgroups, with an average overall survival of 70%. Recurrent medulloblastoma is highly aggressive, treatment-resistant, and usually fatal. In addition, current treatments are highly toxic to the developing brain and surviving patients suffer from lifelong side effects. Therefore, novel therapeutic options are urgently needed. MethodsTo inform risk-based, personalized therapy, we developed a novel platform called DrugSeq, which allows predictions of drug sensitivities in patients across medulloblastoma subgroups. We used a perturbagen-response dataset to calculate transcriptional response signatures for each drug and compared this to patient medulloblastoma tumor gene expression. We then stratified patients by molecular subgroup and used an ANOVA analysis to identify drugs that selectively targeted each subgroup. ResultsWe found distinct differences in transcriptional profiles and predicted drug sensitivity for each medulloblastoma subgroup. We identified several kinase inhibitors, epigenetic inhibitors, and several drugs that have been investigated in drug repositioning studies for cancer. ConclusionsWe posit that DrugSeq may identify novel therapies and facilitate patient stratification in clinical trials, leading to more successful targeted medulloblastoma therapies that improve tumor response while minimizing late toxicities. This computational tool can also be used for other cancers to stratify patients based on any clinical or molecular feature. Key points DrugSeq calculates drug sensitivity for medulloblastoma tumors stratified by subgroup. DrugSeq platform may inform patient stratification strategies in clinical trials. Importance of the StudyMedulloblastoma is the most common malignant pediatric brain tumor. Current standard-of-care typically includes surgical resection, multi-agent chemotherapy, and radiation. However, survival rates vary widely between subgroups, ranging from 45 to 90%, depending on age and molecular features. In addition, surviving children frequently suffer from debilitating late side effects of therapy including neurocognitive impairment, epilepsy, stroke, subsequent cancer, endocrinopathies, and early mortality. Therefore, novel therapeutic options are urgently needed. However, a one-size-fits-all approach for therapy is unlikely to be effective given the well-characterized intertumor heterogeneity of medulloblastoma.

cancer biology↗

bioRxiv2025

Phagosome-mediated anti-bacterial immunity is governed by the proton-activated chloride channel in peritoneal macrophages

The success of phagosome degradation relies on the ability of phagocytes to regulate the maturation of phagosomes. However, its underlying molecular mechanisms remain poorly understood. Here, we identify the proton-activated chloride (PAC) channel as a key negative regulator of phagosome maturation. PAC deletion enhanced phagosomal acidification and protease activities, leading to augmented bacterial killing in large peritoneal macrophages (LPMs) upon Escherichia coli infection in mice. Surprisingly, phagosome degradation also stimulated STING-IRF3-interferon responses and inflammasome activation in LPMs, both of which are enhanced upon PAC deletion. The increased inflammasome activation induced the release of cleaved gasdermin D, which localized to the surface of bacteria in the peritoneum and further contributed to their killing. Finally, enhanced bacterial clearance by PAC-deficient LPMs reduced proinflammatory immune cell infiltration and peritoneal inflammation, resulting in improved survival in mice. Our study thus provides new insights into the molecular mechanism of phagosome maturation and the dynamics of host defense response following phagosome-mediated bacterial degradation in peritoneal macrophages. SummaryThe PAC channel mediates phagosome maturation during bacterial infection in macrophages. PAC deletion promotes phagosome-mediated STING-interferon signaling and inflammasome-mediated gasdermin D secretion during bacterial infection in peritoneal macrophages.

immunology↗

bioRxiv2025

Spatial transcriptomics reveals heterogeneous cell-cell interactions among brain regions in a cuprizone model consistent with multiple sclerosis lesions

The cuprizone (CPZ) model is widely used for modeling demyelination in multiple sclerosis (MS) and for testing potential remyelination therapies. We integrated single-cell and spatial transcriptomics (ST) to fine map the spatial cellular and molecular responses during de and remyelination. ST revealed global demyelination and neuroinflammation in the brain beyond the corpus callosum, with region-specific differences. We identified oligodendroglia and microglia as two major cell types with significant transcriptomic changes in the model. Ligand receptor pairing analyses predicted growth factor and phagocytic pathway enrichment during demyelination, which is consistent with changes in MS lesions. During remyelination, while mature oligodendrocytes nearly reversed their phenotype back to the control state, microglia remained associated with the demyelination phenotype. Finally, astrocytes in the CPZ model had the greatest preservation of disease-associated modules to MS lesions, while the MOL, OPC, and microglia showed moderate to low preservation, which overall suggested that the CPZ model had moderate translatability to chronically active MS lesions.

neuroscience↗

bioRxiv2024

Fate plasticity of interneuron specification

The generation of neuronal subtypes in the mammalian central nervous system is driven by competing genetic programs. The medial ganglionic eminence (MGE) gives rise to two major cortical interneuron (cIN) populations, marked by Somatostatin (Sst) and Parvalbumin (Pvalb), which develop on different timelines. The extent to which external signals influence these identities remains poorly understood. Pvalb-positive cINs are particularly important for regulating cortical circuits through strong perisomatic inhibition, yet they have been difficult to model in vitro. Here we investigated the role of the environment in shaping and maintaining Pvalb cINs. We grafted mouse MGE progenitors into a variety of 2D and 3D co-culture models, including mouse and human cortical, MGE, and thalamic systems with dissociated cells, organoids, organotypic cultures, and conditioned media. Across models, we observed distinct proportions of Sst- and Pvalb-positive cIN descendants. Strikingly, grafting MGE progenitors into 3D human, but not mouse, corticogenesis models led to efficient, non-autonomous differentiation of Pvalb-positive cINs. This differentiation was characterized by upregulation of Pvalb maturation markers, downregulation of Sst-specific markers, and the formation of perineuronal nets. Furthermore, lineage-traced postmitotic Sst-positive cINs, when grafted onto human cortical models, also upregulated Pvalb expression. These results reveal an unexpected level of fate plasticity in MGE-derived cINs, demonstrating that their identities can be dynamically shaped by the surrounding environment.

neuroscience↗

bioRxiv2024

Conservation of an immune homeostasis module in land plants

Calcium-dependent protein kinases (CDPKs) decode cellular calcium transients and play diverse roles in plant growth and stress responses, including immunity. In Arabidopsis thaliana (At, Arabidopsis thereafter), AtCPK28 contributes to immune homeostasis by phosphorylating subgroup IV plant U-box proteins AtPUB22/24/25/26, which target the key immune receptor-like cytoplasmic kinase (RLCK) AtBIK1 for turnover. While this module is conserved in multiple angiosperms, it is unclear if the role of CPK28 in immune homeostasis is conserved more broadly across land plants. Here, we took an evolutionary comparative approach to understand the role of CPK28. We identified a single CPK28 ortholog in the liverwort Marchantia polymorpha, MpCPK28, which exhibits Ca2+-dependent kinase activity that is inhibited by calmodulin in vitro. We identified the subgroup IV plant U-box protein MpPUB20e as a substrate of MpCPK28. MpPUB20e is able to ubiquitinate MpPBLa, the functional ortholog of AtBIK1. We also provide preliminary evidence that MpPBLa undergoes proteasomal degradation in Marchantia, suggesting that optimization of MpPBLa protein accumulation is conserved across land plants. Interestingly, while loss of CPK28 function in multiple angiosperm species results in enhanced immune signaling, we find that Marchantia Mpcpk28 mutant alleles do not display enhanced immune-triggered production of reactive oxygen species or resistance to two pathogens. However, transgenic expression of MpCPK28 was able to restore function in Arabidopsis cpk28-1 mutants, suggesting latent functional conservation of MpCPK28. Furthermore, while AtCPK28-mediated phosphorylation of Thr95/94 on AtPUB25/26 is known to contribute to their activation, we could not observe a functional role for the equivalent residue Thr122 on MpPUB20e. Taken together, our results suggest that post-translational fine-tuning by CPK28 is likely to have refined the PUB-BIK1 module in the vascular plant lineages.

plant biology↗

bioRxiv2024

Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice

Genetic changes and epigenetic modifications are associated with neuronal dysfunction in the pathogenesis of neurodegenerative disorders. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Here, we identified an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element, using convolutional neural network. The enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.

neuroscience↗

bioRxiv2024

Signal transduction pathways controlling Ins2 gene activity and β cell state transitions

Pancreatic {beta} cells exist in low and high insulin gene activity states that are dynamic on a scale of hours to days. Here, we used live 3D imaging, mass spectrometry proteomics, and targeted perturbations of {beta} cell signaling to comprehensively investigate Ins2(GFP)HIGH and Ins2(GFP)LOW {beta} cell states. We identified the two Ins2 gene activity states in intact isolated islets and showed that cells in the same state were more likely to be nearer to each other. We report the proteomes of pure {beta} cells to a depth of 5555 proteins and show that {beta} cells with high Ins2 gene activity had reduced {beta} cell immaturity factors, as well as increased translation. We identified activators of cAMP signaling (GLP1, IBMX) as powerful drivers of transitions from Ins2(GFP)LOW to the Ins2(GFP)HIGH states. Okadaic acid and cyclosporine A had the opposite effects. This study provides new insight into the proteomic profiles and regulation of {beta} cell states.

cell biology↗