Single-cell atlases: shared and tissue-specific cell types across human organs

Nature Reviews Genetics, Год журнала: 2022, Номер 23(7), С. 395 - 410

Опубликована: Фев. 25, 2022

Язык: Английский

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Human prefrontal cortex gene regulatory dynamics from gestation to adulthood at single-cell resolution

Cell, Год журнала: 2022, Номер 185(23), С. 4428 - 4447.e28

Опубликована: Окт. 31, 2022

Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define dynamic trajectories each type, revealing major reconfiguration prenatal-to-postnatal transition in all types followed continuous adulthood identifying regulatory networks guiding developmental programs, states, functions. We uncover links between milestones, characterize diverse timing when cells acquire adult-like identify convergence distinct origins. further their regulators implicated neurological disorders. Finally, using this reference, benchmark identities maturation states organoid models. Together, captures landscape cortical development.

Язык: Английский

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Single-cell brain organoid screening identifies developmental defects in autism

Nature, Год журнала: 2023, Номер 621(7978), С. 373 - 380

Опубликована: Сен. 13, 2023

Abstract The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders 1–4 . Cerebral organoids enable study a context. We have developed CRISPR–human organoids–single-cell RNA sequencing (CHOOSE) system, which uses verified pairs guide RNAs, inducible CRISPR–Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening mosaic organoids. Here we show perturbation 36 high-risk autism spectrum disorder genes related transcriptional regulation uncovers their effects on cell fate determination. find dorsal intermediate progenitors, ventral progenitors upper-layer excitatory neurons are among most vulnerable types. construct developmental gene regulatory network cerebral from transcriptomes chromatin modalities identify disorder-associated perturbation-enriched modules. Perturbing members BRG1/BRM-associated factor (BAF) remodelling complex leads enrichment telencephalon progenitors. Specifically, mutating BAF subunit ARID1B affects transition oligodendrocyte interneuron precursor cells, phenotype confirmed patient-specific induced pluripotent stem cell-derived Our paves way high-throughput phenotypic characterization disease susceptibility organoid models with state, molecular pathway readouts.

Язык: Английский

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SEACells infers transcriptional and epigenomic cellular states from single-cell genomics data

Nature Biotechnology, Год журнала: 2023, Номер 41(12), С. 1746 - 1757

Опубликована: Март 27, 2023

Abstract Metacells are cell groupings derived from single-cell sequencing data that represent highly granular, distinct states. Here we present aggregation of states (SEACells), an algorithm for identifying metacells overcome the sparsity while retaining heterogeneity obscured by traditional clustering. SEACells outperforms existing algorithms in comprehensive, compact and well-separated both RNA assay transposase-accessible chromatin (ATAC) modalities across datasets with discrete types continuous trajectories. We demonstrate use to improve gene–peak associations, compute ATAC gene scores infer activities critical regulators during differentiation. Metacell-level analysis scales large is particularly well suited patient cohorts, where per-patient provides more robust units integration. our reveal expression dynamics gradual reconfiguration landscape hematopoietic differentiation uniquely identify CD4 T activation associated disease onset severity a Coronavirus Disease 2019 (COVID-19) cohort.

Язык: Английский

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The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location

Nature Genetics, Год журнала: 2022, Номер 54(12), С. 1881 - 1894

Опубликована: Дек. 1, 2022

Abstract Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized adults. Their potential heterogeneity at different ages and locations is vastly understudied. Here, through dissecting single-cell transcriptomic, epigenomic spatial architectures a comprehensive cohort patient H3-K27M DMGs, we delineate how age anatomical location shape glioma cell-intrinsic -extrinsic features light shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels maturation dependent on location. reveal previously underappreciated relationship between mesenchymal cancer cell states age, linked to age-dependent differences immune microenvironment. Further, resolve organization DMG populations identify mitotic oligodendroglial-lineage niche. Collectively, our study provides powerful framework for rational modeling therapeutic interventions.

Язык: Английский

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Single-cell analysis of prenatal and postnatal human cortical development

Science, Год журнала: 2023, Номер 382(6667)

Опубликована: Окт. 12, 2023

We analyzed >700,000 single-nucleus RNA sequencing profiles from 106 donors during prenatal and postnatal developmental stages identified lineage-specific programs that underlie the development of specific subtypes excitatory cortical neurons, interneurons, glial cell types, brain vasculature. By leveraging chromatin accessibility data, we delineated enhancer gene regulatory networks transcription factors control commitment lineages. intersecting our results with genetic risk for human diseases, types lineages most vulnerable to insults different disorders, especially autism. find expression up-regulated in female cells are enriched Our study captures molecular progression across development.

Язык: Английский

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Multi-omic single-cell velocity models epigenome–transcriptome interactions and improves cell fate prediction

Nature Biotechnology, Год журнала: 2022, Номер 41(3), С. 387 - 398

Опубликована: Окт. 13, 2022

Язык: Английский

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Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment

Nature, Год журнала: 2023, Номер 622(7982), С. 359 - 366

Опубликована: Сен. 27, 2023

Abstract The assembly of cortical circuits involves the generation and migration interneurons from ventral to dorsal forebrain 1–3 , which has been challenging study at inaccessible stages late gestation early postnatal human development 4 . Autism spectrum disorder other neurodevelopmental disorders (NDDs) have associated with abnormal interneuron 5 but these NDD genes affect migration, how they mediate effects remains unknown. We previously developed a platform in subpallial organoids assembloids 6 Here we integrate CRISPR screening investigate involvement 425 development. first screen aimed revealed 13 candidate genes, including CSDE1 SMAD4 subsequently conducted an more than 1,000 that identified 33 cytoskeleton-related endoplasmic reticulum-related gene LNPK discovered that, during reticulum is displaced along leading neuronal branch before nuclear translocation. deletion interfered this displacement resulted migration. These results highlight power CRISPR-assembloid systematically map onto reveal disease mechanisms.

Язык: Английский

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Purification and characterization of human neural stem and progenitor cells

Cell, Год журнала: 2023, Номер 186(6), С. 1179 - 1194.e15

Опубликована: Март 1, 2023

The human brain undergoes rapid development at mid-gestation from a pool of neural stem and progenitor cells (NSPCs) that give rise to the neurons, oligodendrocytes, astrocytes mature brain. Functional study these cell types has been hampered by lack precise purification methods. We describe method for prospectively isolating ten distinct NSPC developing using cell-surface markers. CD24−THY1−/lo were enriched radial glia, which robustly engrafted differentiated into all three lineages in mouse THY1hi marked unipotent oligodendrocyte precursors committed an oligodendroglial fate, CD24+THY1−/lo excitatory inhibitory neuronal lineages. Notably, we identify functionally characterize transcriptomically THY1hiEGFRhiPDGFRA− bipotent glial (GPC), is lineage-restricted but not neurons. Our provides framework functional neurodevelopment.

Язык: Английский

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Multi-omic profiling of the developing human cerebral cortex at the single-cell level

Science Advances, Год журнала: 2023, Номер 9(41)

Опубликована: Окт. 12, 2023

The cellular complexity of the human brain is established via dynamic changes in gene expression throughout development that mediated, part, by spatiotemporal activity cis-regulatory elements (CREs). We simultaneously profiled and chromatin accessibility 45,549 cortical nuclei across six broad developmental time points from fetus to adult. identified cell type-specific domains which highly correlated with expression. Differentiation pseudotime trajectory analysis indicates at CREs precedes transcription structure play a critical role neuronal lineage commitment. In addition, we mapped temporally specific genetic loci implicated neuropsychiatric traits, including schizophrenia bipolar disorder. Together, our results describe complex regulation composition stages determination shed light on impact alterations disease.

Язык: Английский

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