Biology subjects

Maynard, J.

Publications and source records attributed to Maynard, J..

6 recordsLinked to original sources

bioRxiv2026

COUNTERING AGE-ASSOCIATED ALTERATIONS IN OLIGODENDROCYTE-DERIVED EXTRACELLULAR MATRIX REJUVENATES COGNITION

Efforts to rejuvenate age-related cognitive decline have predominantly targeted neurons, often overlooking non-neuronal cell types in the aging brain. Here, we show that countering alterations in oligodendrocyte-derived extracellular matrix (ECM) in the aging hippocampus restores cognition. We identify broad age-associated transcriptional and proteomic changes in oligodendrocytes, including dysregulation of the matrisome, with marked upregulation of ECM components and associated regulators with age. Among these, we detect an increase in Hyaluronan and proteoglycan link protein 2 (HAPLN2), an oligodendrocyte-derived core matrisome protein that locates specifically at the nodes of Ranvier, in the hippocampus of aged mice and older humans. Hapln2 overexpression in oligodendrocytes of young mice recapitulated age-related memory impairments. Conversely, abrogating the age-related increase in Hapln2 induced synaptic plasticity-related hippocampal transcriptional signatures and improved memory in aged mice. Together, these data define oligodendrocyte-derived ECM remodeling as a hallmark of brain aging that can be targeted to rescue cognitive decline.

neuroscience↗

bioRxiv2025

Multivariate environmental exposures are reflected in whole-brain functional connectivity and cognition in youth

Each individuals complex, multidimensional environment, known as their "exposome", plays an essential role in shaping cognitive neurodevelopment. Understanding the mechanisms whereby childrens exposome influences their development is crucial to facilitate the design of interventions to foster positive developmental trajectories for all youth. Recent work has identified a general exposome factor associated with socio-economic inequality that is strongly related to cognition and individual differences in the spatial organization of functional brain networks in youth. Building on these findings, the current study explores whether alterations in functional connectivity may represent a potential mechanism linking variation in the exposome to cognitive performance. We apply a data-driven, cross-validated, whole-brain machine learning approach, connectome-based statistical inference, to identify patterns of functional connectivity associated with exposome scores among early adolescents enrolled in the Adolescent Brain Cognitive Development (ABCD) Study using data collected during three cognitive tasks and during rest. Additionally, we investigate whether the identified patterns of functional connectivity relate to individual differences in cognitive performance across three domains: General Cognition, Executive Functioning, and Learning/Memory. Models incorporating 10-fold cross-validation over 100 iterations identified consistent functional connections associated with the exposome across task and rest conditions (model performance: ns = 6,137 - 8,391, rs = 0.34 - 0.44, ps <.001). Results were robust across data collection sites and functional connections common across all significant models were associated with cognitive performance across domains (ps < 0.0009). Collectively, these findings reveal that multidimensional environmental exposures are reflected in patterns of functional connectivity and relate to cognitive functioning among youth. HighlightsO_LIPatterns of functional connectivity reflect multivariate environmental exposures. C_LIO_LIConsistent exposome-related connectivity patterns were observed across brain states. C_LIO_LIThe identified general exposome network was associated with cognitive performance across domains. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/688261v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@b5cc3aorg.highwire.dtl.DTLVardef@172f954org.highwire.dtl.DTLVardef@14f0d01org.highwire.dtl.DTLVardef@deccb5_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

An image-based CRISPR screen reveals splicing-mediated control of HP1α condensates

Heterochromatin Protein 1 (HP1) is a fundamental component of constitutive heterochromatin, forming subnuclear condensates whose regulation and function remain poorly understood. Here, we present an image-based CRISPR screen targeting nuclear factors that identifies splicing as a pivotal pathway regulating HP1 condensates. We discovered that unspliced intronic RNA modulates HP1 condensates by interacting co-transcriptionally with HP1. By modulating the intron content, RNA processing restricts HP1-RNA interactions at chromatin, thus enabling heterochromatin organization. Disruption of HP1 condensates due to enhanced interactions with unspliced RNA leads to loss of heterochromatin and the activation of stress response protective genes. We propose that RNA is a central component of heterochromatin that modulates HP1 condensates, and that RNA processing enzymes act as a surveillance mechanism for condensates by dynamically regulating the network of multi-valent interactions between RNA and chromatin factors. This model underscores the crosstalk between chromatin organization, transcription, and RNA processing, potentially governing broader nuclear functions.

genetics↗

bioRxiv2025

O-GlcNAc modifications regulate lamin A tail processing

Lamin A processing is highly regulated, and necessary for proper assembly of the nuclear lamina facilitating its role in nuclear structure and chromatin organization. Pre-lamin A is first farnesylated, and then a short C-terminal peptide is cleaved to produce mature lamin A. O-GlcNAc Transferase (OGT), a glucose sensitive post-translational modification enzyme, is a potential regulator for lamin A processing. To explore the role of OGT in lamin A biogenesis, we examined the effects of OGT levels and OGT inhibition. Variation in OGT dose or inhibition of its activity did not alter endogenous lamin A abundance or distribution. To more directly test the regulatory effects of O-GlcNAcylation on lamin A, we adapted a tail cleavage assay. Mutation of an OGT binding motif and O-GlcNAc modification sites reduced tail cleavage efficiency, suggesting that O-GlcNAcylation promotes lamin A processing. Our findings add to the understanding of the regulation of lamin A cleavage and identify a potential link between glucose metabolism and lamina biogenesis.

cell biology↗

bioRxiv2022

O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors

In mammals, interactions between the bone marrow (BM) stroma and hematopoietic progenitors contribute to bone-BM homeostasis. Perinatal bone growth and ossification provide a microenvironment for the transition to definitive hematopoiesis; however, mechanisms and interactions orchestrating the development of skeletal and hematopoietic systems remain largely unknown. Here, we establish intracellular O-linked {beta}-N-acetylglucosamine (O-GlcNAc) modification as a posttranslational switch that dictates the differentiation fate and niche function of early BM stromal cells (BMSCs). By modifying and activating RUNX2, O-GlcNAcylation promotes osteogenic differentiation of BMSCs and stromal IL-7 expression to support lymphopoiesis. In contrast, C/EBP{beta}-dependent marrow adipogenesis and expression of myelopoietic stem cell factor (SCF) is inhibited by O-GlcNAcylation. Ablating O-GlcNAc transferase (OGT) in BMSCs leads to impaired bone formation, increased marrow adiposity, as well as defective B-cell lymphopoiesis and myeloid overproduction in mice. Thus, the balance of osteogenic and adipogenic differentiation of BMSCs is determined by reciprocal O-GlcNAc regulation of transcription factors, which simultaneously shapes the hematopoietic niche.

physiology↗

bioRxiv2020

Oncogenic gene fusions in non-neoplastic precursors as evidence that bacterial infection initiates prostate cancer

Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers1,2. Infection-driven inflammation is implicated in the formation of ERG+ fusions3, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at time of radical prostatectomy. We identified a high frequency of ERG+ non-neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. We verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tri-color fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole prostate mapping in 3 dimensions confirmed multiple (up to 8) distinct ERG+ precancerous lesions in infected cases. Finally, we identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections initiate driver gene alterations in prostate cancer. Furthermore, infection-induced ERG+ fusions are an early alteration in the carcinogenic process and PIA may serve as a direct precursor to prostate cancer.

cancer biology↗