RESUMEN
The cellular complexity of the human brain is established via dynamic changes in gene expression throughout development that is mediated, in part, by the spatiotemporal activity of cis-regulatory elements (CREs). We simultaneously profiled gene expression and chromatin accessibility in 45,549 cortical nuclei across six broad developmental time points from fetus to adult. We identified cell type-specific domains in which chromatin accessibility is highly correlated with gene expression. Differentiation pseudotime trajectory analysis indicates that chromatin accessibility at CREs precedes transcription and that dynamic changes in chromatin structure play a critical role in neuronal lineage commitment. In addition, we mapped cell type-specific and temporally specific genetic loci implicated in neuropsychiatric traits, including schizophrenia and bipolar disorder. Together, our results describe the complex regulation of cell composition at critical stages in lineage determination and shed light on the impact of spatiotemporal alterations in gene expression on neuropsychiatric disease.
Asunto(s)
Cromatina , Multiómica , Humanos , Cromatina/genética , Cromatina/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos , Diferenciación Celular/genética , Encéfalo/metabolismoRESUMEN
Alzheimer's disease (AD) is the most common form of dementia worldwide, with a projection of 151 million cases by 2050. Previous genetic studies have identified three main genes associated with early-onset familial Alzheimer's disease, however this subtype accounts for less than 5% of total cases. Next-generation sequencing has been well established and holds great promise to assist in the development of novel therapeutics as well as biomarkers to prevent or slow the progression of this devastating disease. Here we present a public resource of functional genomic data from the parahippocampal gyrus of 201 postmortem control, mild cognitively impaired (MCI) and AD individuals from the Mount Sinai brain bank, of which whole-genome sequencing (WGS), and bulk RNA sequencing (RNA-seq) were previously published. The genomic data include bulk proteomics and DNA methylation, as well as cell-type-specific RNA-seq and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) data. We have performed extensive preprocessing and quality control, allowing the research community to access and utilize this public resource available on the Synapse platform at https://doi.org/10.7303/syn51180043.2 .
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Enfermedad de Alzheimer , Giro Parahipocampal , Humanos , Enfermedad de Alzheimer/genética , Bioensayo , MultiómicaRESUMEN
BACKGROUND: Stroke is a leading cause of mortality and disability worldwide. Exosomes, or small extracellular vesicles with signaling properties, have recently been identified as novel mechanisms for stroke treatment. This study aims to use bibliometric techniques to identify current research trends and future directions of exosome-based stroke therapy. METHODS: The Web of Science Core Collection was searched using terms that included "exosome" and all stroke types. Bibliometric data, including authors, publication years, citations, countries/regions, institutions, journals, and Keywords Plus, were extracted directly from the Web of Science Core Collection. Keywords were mapped using VOSviewer. RESULTS: From 2010 to 2021, 424 documents were identified with a total of 12,708 citations. The number of publications increased yearly from 2012 to 2021, the majority of which were research and review articles. China and the United States produced the most publications with Henry Ford Hospital and Oakland University serving as the 2 most highly published research institutions. Documents were published most frequently in the journal Stroke. Keywords Plus analyses revealed 3 main research areas: exosomes as pathogenic mediators, biomarkers, and treatments of stroke. Ischemic stroke was the most prevalent type of stroke included in these studies. CONCLUSIONS: Using bibliometric techniques, this study identified a current and growing interest in the research of exosomes in stroke, particularly in their pathogenic, biomarker, and potential minimally invasive therapeutic properties. Given the high prevalence of ischemic stroke in the current literature, further characterization of exosomes in other stroke types, such as intracerebral hemorrhage, emerges as a future direction for this field of research.
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Exosomas , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Hemorragia Cerebral , BibliometríaRESUMEN
To characterize the dysregulation of chromatin accessibility in Alzheimer's disease (AD), we generated 636 ATAC-seq libraries from neuronal and nonneuronal nuclei isolated from the superior temporal gyrus and entorhinal cortex of 153 AD cases and 56 controls. By analyzing a total of ~20 billion read pairs, we expanded the repertoire of known open chromatin regions (OCRs) in the human brain and identified cell-type-specific enhancer-promoter interactions. We show that interindividual variability in OCRs can be leveraged to identify cis-regulatory domains (CRDs) that capture the three-dimensional structure of the genome (3D genome). We identified AD-associated effects on chromatin accessibility, the 3D genome and transcription factor (TF) regulatory networks. For one of the most AD-perturbed TFs, USF2, we validated its regulatory effect on lysosomal genes. Overall, we applied a systematic approach to understanding the role of the 3D genome in AD. We provide all data as an online resource for widespread community-based analysis.
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Enfermedad de Alzheimer , Cromatina , Enfermedad de Alzheimer/genética , Humanos , Regiones Promotoras Genéticas , Factores de Transcripción/genéticaRESUMEN
Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding population-level variation in enhancer function in the human brain. Besides regulating tissue-specific and cell-type-specific transcription of target genes, enhancers themselves can be transcribed. By jointly analyzing large-scale cell-type-specific transcriptome and regulome data, we cataloged 30,795 neuronal and 23,265 non-neuronal candidate transcribed enhancers. Examination of the transcriptome in 1,382 brain samples identified robust expression of transcribed enhancers. We explored gene-enhancer coordination and found that enhancer-linked genes are strongly implicated in neuropsychiatric disease. We identified expression quantitative trait loci (eQTLs) for both genes and enhancers and found that enhancer eQTLs mediate a substantial fraction of neuropsychiatric trait heritability. Inclusion of enhancer eQTLs in transcriptome-wide association studies enhanced functional interpretation of disease loci. Overall, our study characterizes the gene-enhancer regulome and genetic mechanisms in the human cortex in both healthy and diseased states.
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Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo , Encéfalo , Elementos de Facilitación Genéticos/genética , Humanos , Sitios de Carácter Cuantitativo/genética , Secuencias Reguladoras de Ácidos Nucleicos , Transcriptoma/genéticaRESUMEN
Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes that reduce COVID-19 host susceptibility is a critical next step. Using a translational genomics approach that integrates COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX), and perturbagen signatures, we identified IL10RB as the top candidate gene target for COVID-19 host susceptibility. In a series of validation steps, we show that predicted GReX upregulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes and that in vitro IL10RB overexpression is associated with increased viral load and activation of disease-relevant molecular pathways.
RESUMEN
BACKGROUND: Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes and readily available compounds that reduce COVID-19 host susceptibility is a critical next step. METHODS: We integrate COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX) and perturbargen signatures to identify candidate genes and compounds that reverse the predicted gene expression dysregulation associated with COVID-19 susceptibility. The top candidate gene is validated by testing both its GReX and observed blood transcriptome association with COVID-19 severity, as well as by in vitro perturbation to quantify effects on viral load and molecular pathway dysregulation. We validate the in silico drug repositioning analysis by examining whether the top candidate compounds decrease COVID-19 incidence based on epidemiological evidence. RESULTS: We identify IL10RB as the top key regulator of COVID-19 host susceptibility. Predicted GReX up-regulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes. In vitro IL10RB overexpression is associated with increased viral load and activation of immune-related molecular pathways. Azathioprine and retinol are prioritized as candidate compounds to reduce the likelihood of testing positive for COVID-19. CONCLUSIONS: We establish an integrative data-driven approach for gene target prioritization. We identify and validate IL10RB as a suitable molecular target for modulation of COVID-19 host susceptibility. Finally, we provide evidence for a few readily available medications that would warrant further investigation as drug repositioning candidates.