Simon T Schafer | The Salk Institute (original) (raw)

Papers by Simon T Schafer

Autism spectrum disorders (ASD) display both phenotypic and genetic heterogeneity, impeding the u... more Autism spectrum disorders (ASD) display both phenotypic and genetic heterogeneity, impeding the understanding of ASD and development of effective means of diagnosis and potential treatments. Genes affected by genomic variations for ASD converge in dozens of gene ontologies (GOs), but the relationship between the variations at the GO level have not been well elucidated. In the current study, multiple types of genomic variations were mapped to GOs and correlations among GOs were measured in ASD and control samples. Several ASD-unique GO correlations were found, suggesting the importance of cooccurrence of genomic variations in genes from different functional categories in ASD etiology. Combined with experimental data, several variations related to WNT signaling, neuron development, synapse morphology/function and organ morphogenesis were found to be important for ASD with macrocephaly, and novel co-occurrence patterns of them in ASD patients were found. Further, we applied this gene ontology correlation analysis method to nd genomic variations that contribute to ASD etiology in combination with changes in gene expression and transcription factor binding, providing novel insights into ASD with macrocephaly and a new methodology for the analysis of genomic variation.

2020 Information Theory and Applications Workshop (ITA), 2020

New methods in genomics allow the tracking of single cell transcriptome across tens of thousands ... more New methods in genomics allow the tracking of single cell transcriptome across tens of thousands of genes for hundreds of cells dynamically changing over time. These advancements open new computational problems and provide opportunity to explore new solutions to the interrogation of the transcriptome data in humans and in animal models. Common data analysis pipelines include a dimensionality reduction step to facilitate visualizing the data in two or three dimensions, (e.g. using t-distributed stochastic neighbor embedding (t-SNE)). Such methods reveal structure in high-dimensional data, while aiming at accurately representing global structure of the data. A potential pitfall of some methods is gross data loss when constraining the analyses to gene space data that is not asynchronously changing from day to day, or that express more stable variability of some genes relative to other genes.

Seminars in Cell & Developmental Biology, 2020

Brain organoids are three-dimensional neural aggregates derived from pluripotent stem cells throu... more Brain organoids are three-dimensional neural aggregates derived from pluripotent stem cells through self-organization and recapitulate architectural and cellular aspects of certain brain regions. Brain organoids are currently a highly exciting area of research that includes the study of human brain development, function, and dysfunction in unprecedented ways. In this Review, we discuss recent discoveries related to the generation of brain organoids that resemble diverse brain regions. We provide an overview of the strategies to complement these primarily neuroectodermal models with cell types of non-neuronal origin, such as vasculature and immune cells. Recent transplantation approaches aiming to achieve higher cellular complexity and long-term survival of these models will then be discussed. We conclude by highlighting unresolved key questions and future directions in this exciting area of human brain organogenesis.

Proceedings of the National Academy of Sciences, 2021

Neuronal culture was used to investigate neuronal function in physiological and pathological cond... more Neuronal culture was used to investigate neuronal function in physiological and pathological conditions. Despite its inevitability, primary neuronal culture remained a gold standard method that requires laborious preparation, intensive training, and animal resources. To circumvent the shortfalls of primary neuronal preparations and efficiently give rise to functional neurons, we combine a neural stem cell culture method with a direct cell type-conversion approach. The lucidity of this method enables the efficient preparation of functional neurons from mouse neural progenitor cells on demand. We demonstrate that induced neurons (NPC-iNs) by this method make synaptic connections, elicit neuronal activity-dependent cellular responses, and develop functional neuronal networks. This method will provide a concise platform for functional neuronal assessments. This indeed offers a perspective for using these characterized neuronal networks for investigating plasticity mechanisms, drug scree...

We offer a large collection of well characterized antibodies against neuroscience related protein... more We offer a large collection of well characterized antibodies against neuroscience related proteins. Most of our antibodies are exclusively available at Synaptic Systems and have been developed in-house in close collaboration with reknown experts in the fi eld. Purchase your antibodies directly from the manufacturer and benefi t from our experience and expertise.

Science, 2021

Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reli... more Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell–induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.

Cell Stem Cell, 2021

Summary Sporadic Alzheimer’s disease (AD) exclusively affects elderly people. Using direct conver... more Summary Sporadic Alzheimer’s disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity.

Cell Stem Cell, 2020

Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain ce... more Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin αv (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αvβ5. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αvβ5 inhibition. Collectively, our studies identify integrin αvβ5 as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.

Science, 2019

Non-coding genetic variation is a major driver of phenotypic diversity, but functional interpreta... more Non-coding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined non-coding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer’s disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell type-specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia but not in neurons or astrocytes. These findings revise and expand the genes likely to be influenced by non-coding variants in AD and suggest the probable cell types in which they function.

Unique cell type-specific patterns of activated enhancers can be leveraged to interpret non-codin... more Unique cell type-specific patterns of activated enhancers can be leveraged to interpret non-coding genetic variation associated with complex traits and diseases such as neurological and psychiatric disorders. Here, we have defined active promoters and enhancers for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with regulatory regions in neurons, idiopathic Alzheimer’s disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting GWAS variants in cell type-specific enhancers to gene promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia but not in neurons or astrocytes. These findings revise and expand the genes likely to be influenced by non-coding variants in AD and suggest the probable brain cell types in which they function.One Sentence SummaryIdentification of cell type-specific regulatory...

Brain Structure and Function, 2018

The paper solves the problem of optimal portfolio choice when the parameters of the asset returns... more The paper solves the problem of optimal portfolio choice when the parameters of the asset returns distribution, like the mean vector and the covariance matrix are unknown and have to be estimated by using historical data of the asset returns. The new approach employs the Bayesian posterior predictive distribution which is the distribution of the future realization of the asset returns given the observable sample. The parameters of the posterior predictive distributions are functions of the observed data values and, consequently, the solution of the optimization problem is expressed in terms of data only and does not depend on unknown quantities. In contrast, the optimization problem of the traditional approach is based on unknown quantities which are estimated in the second step leading to a suboptimal solution. We also derive a very useful stochastic representation of the posterior predictive distribution whose application leads not only to the solution of the considered optimization problem, but provides the posterior predictive distribution of the optimal portfolio return used to construct a prediction interval. A Bayesian efficient frontier, a set of optimal portfolios obtained by employing the posterior predictive distribution, is constructed as well. Theoretically and using real data we show that the Bayesian efficient frontier outperforms the sample efficient frontier, a common estimator of the set of optimal portfolios known to be overoptimistic.

Nature communications, Aug 6, 2018

Activity-induced remodeling of neuronal circuits is critical for memory formation. This process r... more Activity-induced remodeling of neuronal circuits is critical for memory formation. This process relies in part on transcription, but neither the rate of activity nor baseline transcription is equal across neuronal cell types. In this study, we isolated mouse hippocampal populations with different activity levels and used single nucleus RNA-seq to compare their transcriptional responses to activation. One hour after novel environment exposure, sparsely active dentate granule (DG) neurons had a much stronger transcriptional response compared to more highly active CA1 pyramidal cells and vasoactive intestinal polypeptide (VIP) interneurons. Activity continued to impact transcription in DG neurons up to 5 h, with increased heterogeneity. By re-exposing the mice to the same environment, we identified a unique transcriptional signature that selects DG neurons for reactivation upon re-exposure to the same environment. These results link transcriptional heterogeneity to functional heterogen...

Cell Stem Cell, 2017

Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differ... more Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differentiation. Nucleoporins are linked with cell-type-specific gene regulation, coupling physical changes in nuclear structure to transcriptional output; but, whether and how they coordinate with key fate-determining transcription factors is unclear. Here we show that the nucleoporin Nup153 interacts with Sox2 in adult NeuPCs, where it is indispensable for their maintenance and controls neuronal differentiation. Genome-wide analyses show that Nup153 and Sox2 bind and co-regulate hundreds of genes. Binding of Nup153 to gene promoters or transcriptional end sites correlates with increased or decreased gene expression, respectively, and inhibiting Nup153 expression alters open chromatin configurations at its target genes, disrupts genomic localization of Sox2, and promotes differentiation in vitro and a gliogenic fate switch in vivo. Together, these findings reveal that nuclear structural proteins may exert bimodal transcriptional effects to control cell fate.

Nature neuroscience, Jun 2, 2016

We longitudinally imaged the developing dendrites of adult-born mouse dentate granule cells (DGCs... more We longitudinally imaged the developing dendrites of adult-born mouse dentate granule cells (DGCs) in vivo and found that they underwent over-branching and pruning. Exposure to an enriched environment and constraint of dendritic growth by disrupting Wnt signaling led to increased branch addition and accelerated growth, which were, however, counteracted by earlier and more extensive pruning. Our results indicate that pruning is regulated in a homeostatic fashion to oppose excessive branching and promote a similar dendrite structure in DGCs.