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.
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.
Abstract
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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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.
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.
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.
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.
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.
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.
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Introduction:
The lack of treatments for intracerebral hemorrhage (ICH) suggests the need for novel preclinical models of this disease. To that end, this study aimed to explore the ...utility of an ICH neural organoid model.
Methods:
Human neural organoids consisting of several cell types, including microglia, were provided by Stem Pharm, Inc. On DIV 21, organoids were treated with human whole blood (n=3 organoids in each condition) for 24 hours. To serve as positive and negative controls, one organoid was treated with lipopolysaccharide (LPS) for 24 hours and three remained untreated. Human IL-6 concentrations were measured in the culture media prior to and after treatments using an enzyme-linked immunosorbent assay (ELISA) and the fold-change from baseline was normalized to the negative control condition. A one-way ANOVA with Dunnett’s test was then performed to compare IL-6 secretion between the control and treatment conditions.
Results:
LPS and blood stimulation both induced IL-6 secretion after 24 hours. The greatest fold increase in IL-6 concentration relative to the control group was observed with 10% blood stimulation (29.76 +/- 7.91, p<0.0001) followed by LPS (23.43 +/- 11.18, p<0.001) and 5% blood (22.56 +/- 7.91, p<0.0001). Significant fold increases in IL-6 secretion were also observed in the lower concentration conditions of 2.5% (15.75 +/- 7.91, p<0.001), 1.25% (11.46 +/- 7.91, p<0.01), and 0.6% blood (11.60 +/- 7.91, p<0.01).
Conclusion:
This preliminary study is the first to explore a neural organoid model of ICH. Comparable to LPS, the observed trends in IL-6 secretion suggest that whole blood is a potent, dose-dependent inducer of organoid inflammation. Given the blood-induced neuroinflammation that occurs during ICH, these initial results support a potential role for neural organoids in ICH modeling. Future work will aim to further characterize the organoid inflammatory response and validate this ICH model system via gene expression analyses.
Summary Background Patients with mixed dyslipidaemia have raised triglycerides, low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol. Augmentation of HDL ...cholesterol by inhibition of the cholesteryl ester transfer protein (CETP) could benefit these patients. We aimed to investigate the effect of the CETP inhibitor, torcetrapib, on carotid atherosclerosis progression in patients with mixed dyslipidaemia. Methods We did a randomised double-blind trial at 64 centres in North America and Europe. 752 eligible participants completed an atorvastatin-only run-in period for dose titration, after which they all continued to receive atorvastatin at the titrated dose. 377 of these patients were randomly assigned to receive 60 mg of torcetrapib per day and 375 to placebo. We made carotid ultrasound images at baseline and at 6-month intervals for 24 months. The primary endpoint was the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Analysis was restricted to 683 patients who had at least one dose of treatment and had at least one follow-up carotid intima-media measurement; they were analysed as randomised. Mean follow-up for these patients was 22 (SD 4·8) months. This trial is registered with ClinicalTrials.gov , number NCT00134238. Findings The change in maximum carotid intima-media thickness was 0·025 (SD 0·005) mm per year in patients given torcetrapib with atorvastatin and 0·030 (0·005) mm per year in those given atorvastatin alone (difference −0·005 mm per year, 95% CI −0·018 to 0·008, p=0·46). Patients in the combined-treatment group had a 63·4% relative increase in HDL cholesterol (p<0·0001) and an 17·7% relative decrease in LDL cholesterol (p<0·0001), compared with controls. Systolic blood pressure increased by 6·6 mm Hg in the combined-treatment group and 1·5 mm Hg in the atorvastatin-only group (difference 5·4 mm Hg, 95% CI 4·3–6·4, p<0·0001). Interpretation Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.
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