Biology subjects

Deans, M.

Publications and source records attributed to Deans, M..

5 recordsLinked to original sources

bioRxiv2025

BRD1 haploinsufficiency alters early neuronal programming and disrupts maturation in human induced glutamatergic neurons

BRD1 is an epigenetic regulator implicated in neurodevelopmental and psychiatric disorders, yet its role in human neuronal differentiation, maturation, and function remains poorly understood. Here we show that BRD1 haploinsufficiency disrupts early neuronal programming, resulting in accelerated maturation and altered neurodevelopmental trajectories in human induced glutamatergic neurons. Transcriptomic profiling reveals an early shift toward neuronal identity, characterized by downregulation of pluripotency markers and persistent upregulation of genes involved in synapse assembly and organization, including GRIA3. Despite this, BRD1+/- neurons form significantly smaller synapses and display increased neuronal activity. Our findings highlight BRD1 as a key regulator of neurodevelopmental timing and synaptic maturation, and network activity reinforcing growing evidence that disruptions in chromatin-mediated control of differentiation and synaptic organization contribute to neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Decoding the transcriptomic signatures of psychological trauma in human cortex and amygdala

Psychological trauma has profound effects on brain function and precipitates psychiatric disorders in vulnerable individuals, however, the molecular mechanisms linking trauma with psychiatric risk remain incompletely understood. Using RNA-seq data postmortem brain tissue of a cohort of 304 donors (N=136 with trauma exposure), we investigated transcriptional signatures of trauma exposures in two cortical regions (dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex) and two amygdala regions (medial amygdala and basolateral amygdala) associated with stress processing and regulation. We focused on dissecting heterogeneity of traumatic experiences in these transcriptional signatures by investigating exposure to several trauma types (childhood, adulthood, complex, single acute, combat, and interpersonal traumas) and interactions with sex. Overall, amygdala regions were more vulnerable to childhood traumas, whereas cortical regions were more vulnerable to adulthood trauma (regardless of childhood experience). Using cell-type-specific expression imputation, we identified a strong transcriptional response of medial amygdala excitatory neurons to childhood trauma, which coincided with dysregulation observed in a human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons exposed to hydrocortisone. We resolved multiscale coexpression networks for each brain region and identified modules enriched in trauma signatures and whose connectivity was altered with trauma. Trauma-associated coexpression modules provide insight into coordinated functional dysregulation with different traumas and point to potential gene targets for further dissection. Together, these data provide a characterization of the long-lasting human encoding of traumatic experiences in corticolimbic regions of human brain.

neuroscience↗

bioRxiv2024

Dynamic stress- and inflammatory-based regulation of psychiatric risk loci in human neurons

The immune environment influences neurodevelopment and subsequent clinical trajectories for psychiatric outcomes in childhood and adolescence. Yet it remains unclear if the impact of maternal and fetal immune activation varies with distinct polygenic risk profiles. Therefore, here we catalogue genotype and environment (GxE) interactions, contrasting allele-specific regulatory activity between inflammatory cues. We report a cue-specific neuronal massively parallel reporter assay (MPRA) of 152 loci from genome-wide association study (GWAS) linked to ten brain traits/disorders, empirically dissecting the impact of interleukin-6 (IL-6) and interferon-alpha (IFN) on transcriptional activity. In human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons, 1,156 active candidate regulatory risk sequences (MPRA-active CRSs) are resolved, including 267 with variant-specific effects (MPRA-emVars) and 61 with variant-by-cytokine interaction effects (interaction MPRA-emVars). Broadly, neuronal immune-mediated regulatory activity is associated with differences in transcription factor binding and chromatin accessibility, the gene targets of which show pleiotropic enrichments for brain, metabolic, and immune disorders. Dynamic genetic regulation mediates neuroimmune effects, informing our understanding of the genomics of psychiatric and neurological traits, mechanisms governing pleiotropy across disorders, and how immune mechanisms mediate genetic risk.

genetics↗

bioRxiv2023

Large-scale annotated dataset for cochlear hair cell detection and classification

Our sense of hearing is mediated by cochlear hair cells, localized within the sensory epithelium called the organ of Corti. There are two types of hair cells in the cochlea, which are organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains a few thousands of hair cells, and their survival is essential for our perception of sound because they are terminally differentiated and do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. However, the sheer number of cells along the cochlea makes manual quantification impractical. Machine learning can be used to overcome this challenge by automating the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, human, pig and guinea pig cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 90,000 hair cells, all of which have been manually identified and annotated as one of two cell types: inner hair cells and outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to supply other groups within the hearing research community with the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.

neuroscience↗

bioRxiv2019

Nanoscopic Clustering of Neuroligin-3 and Neuroligin-4X Regulates Growth Cone Organization and Size

The cell-adhesion proteins neuroligin-3 and neuroligin-4X (NLGN3/4X) have well described roles in synapse formation. NLGN3/4X are also expressed highly during neurodevelopment. However, the role these proteins play during this period is unknown. Here we show that NLGN3/4X localized to the leading edge of growth cones where itpromoted neuritogenesis in immature human neurons. Super-resolution microscopyrevealed that NLGN3/4X clustering induced growth cone enlargement and influenced actin filament organization. Critically, these morphological effects were not induced by Autism spectrum condition (ASC)-associated NLGN3/4X variants. Finally, actin regulators p21-activated kinase 1 (PAK1) and cofilin were found to be activated by NLGN3/4X and involved in mediating the effects of these adhesion proteins on actin filaments, growth cones, and neuritogenesis. These data reveal a novel role for NLGN3 and NLGN4X in the development of neuronal architecture, which may be altered in the presence of ASD-associated variants.

neuroscience↗