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Science Journals RESEARCH ◥ potential to unravel the molecular programs that RESEARCH ARTICLE SUMMARY underlie cell specification in the human cerebral cortex and, by temporally mapping disease risk NEUROGENETICS onto these changes, to identify cell types and Chromatin accessibility dynamics in a model periods of increased disease susceptibility. RESULTS: We used three-dimensional (3D) di- of human forebrain development rected differentiation of human pluripotent stem cells into dorsal and ventral forebrain do- Alexandro E. Trevino*, Nasa Sinnott-Armstrong*, Jimena Andersen*, Se-Jin Yoon, Nina Huber, mains and applied the assay for transposase- Jonathan K. Pritchard, Howard Y. Chang, William J. Greenleaf†, Sergiu P. Pașca† accessible chromatin with high-throughput sequencing (ATAC-seq) in combination with RNA-sequencing (RNA-seq) to map the epige- INTRODUCTION: The cerebral cortex is respon- neurodevelopmental disease, including autism netic and gene expression signatures of neu- sible for higher-order functions in the nervous spectrum disorders and intellectual disability. ronal and glial cell lineages over 20 months system and has undergone substantial expan- in vitro. We show, through direct comparison sion in size in primates. The development of RATIONALE: Human forebrain development is, with primary brain tissue from our study and theforebrain,includingtheassemblyofthe to a large extent, inaccessible for cellular-level ◥ several epigenetic data- expanded human cerebral cortex, is a lengthy study, direct functional investigation, or manip- ON OUR WEBSITE sets, that human stem – Downloaded from process that involves the diversification and ulation. The lack of availability of primary brain Read the full article cell derived 3D forebrain expansion of neural progenitors, the generation tissue samples—in particular, at later stages— at http://dx.doi. organoids recapitulated and positioning of layer-specific glutamatergic as well as the limitations of conventional in org/10.1126/ in vivo chromatin acces- neurons, the cellular migration of g-amino- vitro cellular models have precluded a detailed science.aay1645 sibility patterns over time. .................................................. butyric acid (GABA)–ergic neurons, and the mechanistic understanding of corticogenesis We then integrated these formation and maturation of glial cells. Dis- in healthy and disease states. Therefore, track- data to discover putative enhancer-gene link- ruption of these cellular events by either ge- ing epigenetic changes in specific forebrain ages and lineage-specific transcription factor http://science.sciencemag.org/ netic or environmental factors can lead to cell lineages over long time periods, has the regulators, including a diverse repertoire of factors that may control cortical specifica- Human cellular model of forebrain development Developmental mapping tion. We validated protein expression of some Cortical spheroids (hCS) Cell isolation of these transcription factors using immuno- fluorescence, confirming cellular and temporal dynamics in both primary tissue and fore- stage brain organoids. Next, we used this resource Subpallial spheroids (hSS) to map genes and genetic variants associated Glial In vivo hiPS cells with schizophrenia and autism spectrum dis- orders to distinct accessibility patterns to Neuronal reveal cell types and periods of susceptibility. on January 24, 2020 25 days 595 days In vitro stage Last, we identified a wave of chromatin re- Cell type–specific chromatin accessibility Enhancer–gene correlations modeling during cortical neurogenesis, during which a quarter of regulatory regions are active, and then highlighted transcription factors that may drive these developmental changes. ATAC–seq CONCLUSION: Using long-term 3D neural dif- ferentiation of stem cells as well as primary Open braintissuesamples,wefoundthatorganoids chromatin intrinsically undergo chromatin state transi- regions tions in vitro that are closely related to human forebrain development in vivo. Leveraging this Chromatin dynamics in human corticogenesis Disease enrichment platform, we identified epigenetic alterations GWAS putatively driven by specific transcription factors Neurogenesis SFARI genes’ binding sites . anddiscoveredadynamicperiodofchromatin NEUROD2 . remodeling during human cortical neurogen- . POU3F2 (BRN2) . esis. Finally, we nominated several key transcrip- . tion factors that may coordinate over time to . drive these changes and mapped cell type– TBR1 . specific disease-associated variation over time MEF2C . Chromatin accessibility and in specific cell types.▪ 0 79 262 Motif activity Stage (days) SCZ ASD ALZ The list of author affiliations is available in the full article online. Developing a human cellular model of forebrain development to study chromatin dynamics. ATAC-seq *These authors contributed equally to this work. and RNA-seq studies over long-term differentiation of human pluripotent stem cells into forebrain †Corresponding author. Email: [email protected] (W.J.G.); [email protected] (S.P.P.) organoids and in primary brain tissue samples reveal dynamic changes during human corticogenesis, Cite this article as: A. E. Trevino et al., Science 367, including a wave associated with neurogenesis, and identify disease-susceptible cell types and stages. eaay1645 (2020). Trevino et al., Science 367, 404 (2020) 24 January 2020 1of1 RESEARCH ◥ emergence of radial glial progenitors (Fig. 1B RESEARCH ARTICLE andfig.S1A),followedbytheprogressivegen- eration of deep and superficial glutamatergic NEUROGENETICS neurons (Fig. 1C and fig. S1B), and last, the generation and maturation of astrocytes (Fig. Chromatin accessibility dynamics in a model 1D and fig. S1, C and D). Ventral forebrain hSSs generate glutamic acid decarboxylase of human forebrain development 67+ (GAD67+)andGABA+ interneurons (Fig. 1E and fig. S1E) (25). Alexandro E. Trevino1,2*, Nasa Sinnott-Armstrong3*, Jimena Andersen2,4*, Se-Jin Yoon2,4, Nina Huber4, We collected 117 ATAC-seq (assay for Jonathan K. Pritchard3,5,6, Howard Y. Chang3,6,7,8, William J. Greenleaf3,9,10†, Sergiu P. Pașca4† transposase-accessible chromatin with high- throughput sequencing) samples and 54 RNA- Forebrain development is characterized by highly synchronized cellular processes, which, if perturbed, sequencing (RNA-seq) samples from hCSs and can cause disease. To chart the regulatory activity underlying these events, we generated a hSSs derived from 7 hiPS cell lines (tables S1 and map of accessible chromatin in human three-dimensional forebrain organoids. To capture corticogenesis, S2). At early stages, we isolated purified nuclei we sampled glial and neuronal lineages from dorsal or ventral forebrain organoids over 20 months from whole, undissociated spheroids (28). Af- in vitro. Active chromatin regions identified in human primary brain tissue were observed in organoids at ter day 79, we purified glial and neuronal cell different developmental stages. We used this resource to map genetic risk for disease and to explore lineages by either surface marker immuno- evolutionary conservation. Moreover, we integrated chromatin accessibility with transcriptomics to panning or fluorescence-activated cell sorting identify putative enhancer-gene linkages and transcription factors that regulate human corticogenesis. (FACS). For immunopanning, glial lineage Downloaded from Overall, this platform brings insights into gene-regulatory dynamics at previously inaccessible stages of cells were isolated by using an antibody against human forebrain development, including signatures of neuropsychiatric disorders. HepaCAM, and neuronal lineage cells were iso- lated by using an antibody against Thy1 (CD90) (24, 29). For FACS, cells were labeled with he assembly of the human cerebral cor- proxy for regulatory potential (10). Therefore, viral reporters driven by the human glial fi- tex is a dynamic and lengthy process that defining accessibility across human brain cell brillary acidic protein (GFAP) promoter or http://science.sciencemag.org/ begins during early gestation and con- lineages and time could provide understand- the synapsin 1 (SYN1) promoter [pLV-GFAP:: T tinues postnatally (1). It is characterized ing of gene-regulatory principles and disease enhanced green fluorescent protein (eGFP) by the inside-out generation of neurons signatures in the human forebrain. andadeno-associatedvirus(AAV)–SYN1:: in the pallium from progenitors, followed by the Previous studies have begun to define the mCherry, respectively] (Fig. 1A) (30). We generation and maturation of astrocytes and transcriptome and epigenome of the develop- confirmed the specificity of these markers other glial cells. g-aminobutyric acid (GABA)– ing human forebrain, including characteriza- using a single-cell RNA-seq dataset (fig. S2). ergic interneurons, born in the subpallium, tion of spatiotemporal gene expression in the We refer to GFAP+ or HepaCAM+ cells as glial migrate into the cerebral cortex, where they cortex (11–14), the molecular signature of cor- lineagecells,whichmayencompassradialglia, integrate to form circuits (2, 3). Although tical progenitors (15, 16), epigenetics of early outer radial glia, and mature astrocytes, de- genetic and environmental perturbations of brain development (17), and the impact of re- pending on the differentiation stage. We refer + + corticogenesis can cause severe neurodevel- cently evolved enhancers on gene expression to SYN1 and Thy1 cells as neuronal lineage on January 24, 2020 opmental disease (4), a detailed understand-
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