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Decoding gene regulation in the fly brain

ABSTRACT: The Drosophila brain is a work horse in neuroscience. Single-cell transcriptome analysis, 3D morphological classification, and detailed mapping of the connectome have revealed an immense diversity of neuronal and glial cell types that underlie the wide array of functional and behavioral traits in the fruit fly. The developmental trajectories of each of these cell types, from neuroblast to mature neuron or glial cell, as well as their maintenance and plasticity in the adult brain, are controlled by gene regulatory networks (GRNs) In this study, we profiled chromatin accessibility of 240,000 single cells, spanning nine developmental time points from larval, pupal, and adult brains, and integrated this data with single-cell transcriptomes. This atlas reveals the regulatory connections between genomic enhancers and the single-cell transcriptomes for more than 80 cell types in the fly brain. Each cell type is characterized by a unique chromatin accessibility landscape, with thousands of specific regulatory regions, summing to a total of 95,931 regulatory regions that are used in the brain. Exploiting this resource, we find that the combination of expressed transcription factors is reflected by their respective motif architecture within cell type-specific enhancers.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE163697 | GEO | 2021/08/10

REPOSITORIES: GEO

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A Single Cell Transcriptomic Analysis of Human Neocortical Development

Project description:<p>Defining the number, proportion, or lineage of distinct cell types in the developing human brain is an important goal of modern brain research. We produced single cell transcriptomic profiles for 40,000 cells at mid-gestation to define deep expression profiles corresponding to all known major cell types at this developmental period and compare this with bulk tissue profiles. We identified multiple transcription factors (TFs) and co-factors expressed in specific cell types, including multiple new cell-type-specific relationships, providing an unprecedented resource for understanding human neocortical development and evolution. This includes the first single-cell characterization of human subplate neurons and subtypes of developing glutamatergic and GABAergic neurons. We also used these data to deconvolute single cell regulatory networks that connect regulatory elements and transcriptional drivers to single cell gene expression programs in the developing CNS. We characterized major developmental trajectories that tie cell cycle progression with early cell fate decisions during early neurogenesis. Remarkably, we found that differentiation occurs on a transcriptomic continuum, so that differentiating cells not only express the few key TFs that drive cell fates, but express broad, mixed cell-type transcriptomes prior to telophase. Finally, we mapped neuropsychiatric disease genes to specific cell types, implicating dysregulation of specific cell types in ASD, ID, and epilepsy, as the mechanistic underpinnings of several neurodevelopmental disorders. Together these results provide an extensive catalog of cell types in human neocortex and extend our understanding of early cortical development, human brain evolution and the cellular basis of neuropsychiatric disease.</p>

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Single-cell transcriptomics reveals glial cells integrate homeostatic and circadian processes to drive sleep-wake cycle

Project description:The sleep-wake cycle is determined by a circadian and a sleep homeostatic process. However, the molecular impact of these two processes and their interaction on different cell populations in the brain remain unknown. To fill this gap, we have profiled the single-cell transcriptome of adult fruit fly brains across the sleep-wake cycle and different circadian times. We show cell type-specific transcriptomic changes between sleep/wakefulness states, different levels of sleep drive, and varying circadian times, with glial cells displaying the largest variations. Furthermore, the cell types whose transcriptomic dynamics correlate with the sleep homeostat or circadian clock are largely non-overlapping, with the exception of glial cells. Diminishing the circadian clock only in glial cells impairs the homeostatic sleep rebound after sleep deprivation. These findings reveal a comprehensive picture of different effects of sleep homeostatic and circadian processes on different cell types and define glial cells as the interaction sites of these two processes to determine sleep-wake dynamics.

2023-11-29 | GSE221239 | GEO

A comparative atlas of single-cell chromatin accessibility in the human brain

Project description:A comparative atlas of single-cell chromatin accessibility in the human brainRecent advances in single-cell transcriptomics have illuminated the diverse neuronal and glial cell types within the human brain. However, the regulatory programs governing cell identity and function remain unclear. Using a single-nucleus assay for transposase-accessible chromatin using sequencing (ATAC-seq), we explored open chromatin landscapes across 1.1 million cells in 42 brain regions from three adults. Integrating this data unveiled 107 distinct cell types and their specific utilization of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly a third of the cCREs demonstrated conservation and chromatin accessibility in the mouse brain cells. We reveal strong links between specific brain cell types and neuropsychiatric disorders including schizophrenia, bipolar disorder, Alzheimer’s disease (AD), and major depression, and have developed deep learning models to predict the regulatory roles of noncoding risk variants in these disorders.

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Effects of Overexpression of Dube3a in Drosophila Brain

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2019-12-31 | GSE138562 | GEO

An Atlas of Gene Regulatory Elements in Adult Mouse Cerebrum

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Project description:Mitochondrial composition varies by organ and their constituent cell types. This mitochondrial diversity likely determines variations in mitochondrial function. However, the heterogeneity of mitochondria in the brain remains underexplored despite the large diversity of cell types in neuronal tissue. Here, we used molecular systems biology tools to address whether mitochondrial composition varies by brain region and neuronal cell type. We reasoned that proteomics and transcriptomics of microdissected brain regions combined with analysis of single cell mRNA sequencing could reveal the extent of mitochondrial compositional diversity. We selected nuclear encoded gene products forming complexes of fixed stoichiometry, such as the respiratory chain complexes and the mitochondrial ribosome, as well as molecules likely to perform their function as monomers, such as the family of SLC25 transporters. We found that only the proteome encompassing these nuclear-encoded mitochondrial genes and obtained from microdissected brain tissue segregated the hippocampus, striatum, and cortex from each other. Nuclear-encoded mitochondrial transcripts could only segregate cell types and brain regions when the analysis was performed at the single cell level. In fact, single cell mitochondrial transcriptomes were able to distinguish glutamatergic and distinct types of GABAergic neurons from one another. Within these cell categories, unique SLC25A transporters were able to identify distinct cell subpopulations. Our results demonstrate heterogeneous mitochondrial composition across brain regions and cell types. We postulate that mitochondrial heterogeneity influences regional and cell type specific mechanisms in health and disease.

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Transcriptional Reprogramming of Brain Cells Under Anesthesia in wt and Alzheimer's Disease mouse model

Project description:In this study, we addressed the following questions: Which brain cell types are transcriptionally reprogrammed under anesthesia? What is the cell-type specific response to anesthesia? And how does the response change between WT and AD in mouse models? We profiled by single nucleus RNA-sequencing (snRNA-seq) of hippocampus brain region samples from awake and anesthetized wild-type (WT) and APP/PS1 AD mouse model. We found a strong and robust transcriptional switch in all glial cell types in the anesthetized mice and in specific neuronal sub-types. Comparing WT to AD mice uncovered an AD-specific transcriptional response to anesthesia in glial cells and in specific neuronal sub-types. These findings provide new insights on the molecular changes occurring in the anesthetized brain and how they are altered in AD.

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Project description:The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across¬ distinct cell-types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer’s Disease (AD), accessible through our intuitive web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering vast cellular heterogeneity. We identified cell-type specific, disease-associated candidate cis-regulatory elements and their candidate target genes, including an oligodendrocyte-associated regulatory module containing links to APOE and CLU. We describe cis-regulatory relationships in specific cell-types at AD risk loci defined by genome wide association studies (GWAS), demonstrating the utility of this multi-omic single-nucleus approach. Trajectory analysis of glial populations identified disease-relevant transcription factors, like SREBF1 and their regulatory targets. Further, we introduce scWGCNA, a co-expression network analysis strategy robust to the sparsity of single-cell data, to perform a systems-level meta-analysis of AD transcriptomics.

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