Astrocytes and neurons share brain region-specific transcriptional signatures (RNAseq: NeuronsP0)
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ABSTRACT: Neuronal cell diversity is essential to endow distinct brain regions with specific functions. During development, progenitors within these regions are characterised by specific gene expression programs, contributing to the generation of diversity in postmitotic neurons and glia. While the region-specific molecular diversity of neurons and astrocytes is increasingly understood, whether these cells share region-specific programs remains unknown. Here, we show that in the neocortex and thalamus, neurons and astrocytes express shared region-specific transcriptional and epigenetic signatures. These signatures not only distinguish cells across brain regions but are also detected across substructures within regions, such as distinct thalamic nuclei, where clonal analysis reveals the existence of common nucleus-specific progenitors for neurons and glia. Consistent with their shared molecular signature, regional specificity is maintained following astrocyte-to-neuron reprogramming. A detailed understanding of these regional-specific signatures may thus inform strategies for future cell-based brain repair.
Project description:Neuronal cell diversity is essential to endow distinct brain regions with specific functions. During development, progenitors within these regions are characterised by specific gene expression programs, contributing to the generation of diversity in postmitotic neurons and glia. While the region-specific molecular diversity of neurons and astrocytes is increasingly understood, whether these cells share region-specific programs remains unknown. Here, we show that in the neocortex and thalamus, neurons and astrocytes express shared region-specific transcriptional and epigenetic signatures. These signatures not only distinguish cells across brain regions but are also detected across substructures within regions, such as distinct thalamic nuclei, where clonal analysis reveals the existence of common nucleus-specific progenitors for neurons and glia. Consistent with their shared molecular signature, regional specificity is maintained following astrocyte-to-neuron reprogramming. A detailed understanding of these regional-specific signatures may thus inform strategies for future cell-based brain repair.
Project description:Astrocytes within specific brain regions contribute uniquely to regional circuits for higher-order brain function through interactions with local neurons. The regional diversification of astrocytes is dictated by their embryonic origin, yet the mechanisms governing their regional allocation remain unknown. Here we show that allocation of astrocytes to specific brain regions requires the transcription factor 4 (Tcf4) mediated fate restriction during brain development. Loss of Tcf4 in ventral telencephalic neural progenitors alters the fate of oligodendrocyte precursors to transient intermediate astrocyte precursor cells, resulting in mislocated astrocytes in the dorsal neocortex. These ectopic astrocytes originated from the ventral telencephalon engage with neurons and acquire features reminiscent of local neocortical astrocytes. Furthermore, Tcf4 functions as a suppressor of astrocyte fate during differentiation of oligodendrocyte precursors, thereby restricting the fate to oligodendrocyte lineage. Our study reveals that fate restriction governs regional astrocyte allocation, contributing to astrocyte diversification across brain regions.
Project description:The goals of this study are to profile the molecular signatures of astrocytes from four brain regions (olfactory bulb, hippocampus, cortex, and brainstem) and determine if differential transcription factor enrichment may play a role in shaping astrocyte spatial diversity. We performed RNA-seq on astrocytes from the olfactory bulb, hippocampus, cortex, and brainstem, and determined region-specific molecular signatures. Using transcription factor motif discovery analysis on each region-specific gene signature we uncovered universal and region-specific transcription factor expression profiles.
Project description:We queried a songbird brain to discover behaviorally regulated transcriptional mechanisms relevant for speech behavior. About 10% of zebra finch genes showed regulation during singing, and most were brain-region specific. We propose that the brain-regional diversity of the singing-regulated gene networks is derived both from differential combinatorial binding of transcription factors and the epigenetic state of these genes before singing begins. To test this hypothesis, we measured H3K27ac two brain regions that participate in song production. The examination of H3K27ac in two brain regions of zebra finch in singing and silent conditions
Project description:Astrocytes exhibit a high molecular diversity within the same, as well as across different brain regions. Moreover, astrocytes are characterized by a region-specific role in the regulation of neuronal circuitries, which might be affected by specific diseases. Regarding metabolic control, selective perturbations in astrocytes trigger multiple alterations in energy balance and glucose homeostasis. Using RNA sequencing, we showed that astrocytes have a distinct transcriptomic profile dependent on their anatomical location in the brain, which is affected by hypercaloric diet.
Project description:The epigenome of human brain cells encompasses key information in understanding brain function in both healthy and diseased states. To further explore this, we used ATAC-seq to profile chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes), from three different regions of the brain. Chromatin accessibility was found to vary vastly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the greatest regional variability. Transcription factor footprinting pointed to cell-specific transcriptional regulators and inferred cell-specific regulation of protein coding genes, long intergenic noncoding RNAs, and microRNAs. In vivo transgenic mouse experiments validated the cell type specificity of a number of human-derived regulatory sequences. Open chromatin regions in glutamatergic neurons were enriched for neuropsychiatric risk variants, particularly those associated with schizophrenia. Combining differential chromatin accessibility analysis using ATAC-seq data from bulk tissue increased our statistical power to confirm glutamatergic neurons as the cell type most affected in schizophrenia. Jointly, these findings illustrate the utility of studying the cell type specific epigenome in complex tissues such as the human brain and implicate an association among chromatin accessibility in glutamatergic neurons and genetic risk for schizophrenia.
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.