Single-cell genomics and regulatory networks for 388 human brains

Science, Год журнала: 2024, Номер 384(6698)

Опубликована: Май 23, 2024

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into resource comprising >2.8 million nuclei from prefrontal cortex across 388 individuals. For 28 cell types, assessed population-level variation in expression and chromatin families drug targets. We identified >550,000 type-specific regulatory elements >1.4 single-cell quantitative trait loci, which used to build cell-type cell-to-cell communication networks. These networks manifest cellular changes aging neuropsychiatric disorders. further constructed an integrative model accurately imputing simulating perturbations; prioritized ~250 disease-risk genes targets with associated types.

Язык: Английский

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Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood

Science, Год журнала: 2024, Номер 384(6698)

Опубликована: Май 23, 2024

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study posttraumatic stress disorder (PTSD) and major depressive (MDD) included the central nucleus amygdala, hippocampal dentate gyrus, medial prefrontal cortex (mPFC). Genes exons within mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal synaptic regulation, hormones. Multiomic factor gene network analyses provided underlying genomic structure. Single RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) non-neuronal cell types. Analyses brain-blood intersections >50,000 UK Biobank participants were conducted along with fine-mapping results PTSD MDD genome-wide association studies distinguish risk from processes. data suggest shared distinct both propose potential therapeutic targets biomarkers.

Язык: Английский

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Benchmark of cellular deconvolution methods using a multi-assay dataset from postmortem human prefrontal cortex

Genome biology, Год журнала: 2025, Номер 26(1)

Опубликована: Апрель 7, 2025

Язык: Английский

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Spatiotemporal analysis of gene expression in the human dentate gyrus reveals age-associated changes in cellular maturation and neuroinflammation

Cell Reports, Год журнала: 2025, Номер 44(2), С. 115300 - 115300

Опубликована: Фев. 1, 2025

The dentate gyrus of the hippocampus is important for many cognitive functions, including learning, memory, and mood. Here, we present transcriptome-wide spatial gene expression maps human investigate age-associated changes across lifespan. Genes associated with neurogenesis extracellular matrix are enriched in infants decline throughout development maturation. Following infancy, inhibitory neuron markers increase, cellular proliferation decrease. We also identify spatio-molecular signatures that support existing evidence protracted maturation granule cells during adulthood increases neuroinflammation-related expression. Our findings notion hippocampal neurogenic niche undergoes major following infancy molecular regulators brain aging glial- neuropil-enriched tissue.

Язык: Английский

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Spatial Transcriptomics: Biotechnologies, Computational Tools, and Neuroscience Applications

Small Methods, Год журнала: 2025, Номер unknown

Опубликована: Янв. 6, 2025

Spatial transcriptomics (ST) represents a revolutionary approach in molecular biology, providing unprecedented insights into the spatial organization of gene expression within tissues. This review aims to elucidate advancements ST technologies, their computational tools, and pivotal applications neuroscience. It is begun with historical overview, tracing evolution from early image-based techniques contemporary sequence-based methods. Subsequently, methods essential for data analysis, including preprocessing, cell type annotation, clustering, detection spatially variable genes, cell-cell interaction 3D multi-slices integration are discussed. The central focus this application neuroscience, where it has significantly contributed understanding brain's complexity. Through ST, researchers advance brain atlas projects, gain development, explore neuroimmune dysfunctions, particularly tumors. Additionally, enhances neuronal vulnerability neurodegenerative diseases like Alzheimer's neuropsychiatric disorders such as schizophrenia. In conclusion, while already profoundly impacted challenges remain issues enhancing sequencing technologies developing robust tools. underscores transformative potential paving way new therapeutic research.

Язык: Английский

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Stereo-seq of the prefrontal cortex in aging and Alzheimer’s disease

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 8, 2025

Aging increases the risk for Alzheimer's disease (AD), driving pathological changes like amyloid-β (Aβ) buildup, inflammation, and oxidative stress, especially in prefrontal cortex (PFC). We present first subcellular-resolution spatial transcriptome atlas of human (PFC), generated with Stereo-seq from six male AD cases at varying neuropathological stages age-matched controls. Our analyses revealed distinct transcriptional alterations across PFC layers, highlighted disruptions laminar structure, exposed AD-related shifts layer-to-layer cell-cell interactions. Notably, we identified genes highly upregulated stressed neurons nearby glial cells, where diminished stress-response interactions that promote Aβ clearance. Further, cell-type-specific co-expression analysis three neuronal modules linked to neuroprotection, protein dephosphorylation, regulation, all downregulated as progresses. ZNF460 a transcription factor regulating these modules, offering potential therapeutic target. In summary, this provides valuable insight into AD's molecular mechanisms. (AD). Here, authors AD, revealing alterations.

Язык: Английский

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Organizational Principles of the Primate Cerebral Cortex at the Single‐Cell Level

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 23, 2025

Abstract The primate cerebral cortex, the major organ for cognition, consists of an immense number neurons. However, organizational principles governing these neurons remain unclear. By accessing single‐cell spatial transcriptome over 25 million neuron cells across entire macaque it is discovered that distribution within cortical layers highly non‐random. Strikingly, three‐quarters are located in distinct neuronal clusters. Within clusters, different cell types tend to collaborate rather than function independently. Typically, excitatory clusters mainly consist excitatory‐excitatory combinations, while inhibitory primarily contain excitatory‐inhibitory combinations. Both cluster have roughly equal numbers each layer. Importantly, most and form partnerships, indicating a balanced local network correlating with specific functional regions. These conserved mouse findings suggest brain regions cortex may exhibit similar mechanisms at population level.

Язык: Английский

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Topic modeling analysis of the Allen Human Brain Atlas

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 26, 2025

The human brain is a complex interconnected structure controlling all elementary and high-level cognitive tasks. It composed of many regions that exhibit specific distributions cell types distinct patterns functional connections. This complexity rooted in differential transcription. constituent different express distinctive combinations genes as they develop mature, ultimately shaping their state adulthood. How precisely the genetic information anatomical structures connected to underlying biological functions remains an open question modern neuroscience. A major challenge identification "universal patterns", which do not depend on particular individual, but are instead basic structural properties shared by brains. Despite vast amount gene expression data available at both bulk single-cell levels, this task challenging, mainly due lack suitable mining tools. In paper, we propose approach address issue based hierarchical version Stochastic Block Modeling. Thanks its choice priors, method particularly effective identifying these universal features. We use laboratory test our algorithm dataset obtained from six independent brains Allen Human Brain Atlas. show proposed indeed able identify much better than more traditional algorithms such Latent Dirichlet Allocation or Weighted Correlation Network Analysis. probabilistic association between samples find well represents known organization. Moreover, leveraging peculiar "fuzzy" sets with method, examples transcriptional post-transcriptional pathways associated regions, highlighting potential approach.

Язык: Английский

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Integrative genomics approach identifies glial transcriptomic dysregulation and risk in the cortex of individuals with Alcohol Use Disorder

Biological Psychiatry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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White matter damage and degeneration in traumatic brain injury

Trends in Neurosciences, Год журнала: 2024, Номер 47(9), С. 677 - 692

Опубликована: Авг. 10, 2024

Traumatic brain injury (TBI) is a complex condition that can resolve over time but all too often leads to persistent symptoms, and the risk of poor patient outcomes increases with aging. TBI damages neurons long axons within white matter tracts are critical for communication between regions; this causes slowed information processing neuronal circuit dysfunction. This review focuses on after multifactorial processes underlie damage, potential recovery, progression degeneration. A multiscale perspective across clinical preclinical advances presented encourage interdisciplinary insights from whole-brain neuroimaging down cellular molecular responses axons, myelin, glial cells tissue.

Язык: Английский

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