Neuronal activity induced by BDNF prompts chromatin remodeling at regulatory elements associated with neuropsychiatric traits [mouse]
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PROVIDER: PRJNA702471 | ENA |
REPOSITORIES: ENA
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Project description:Neuronal activity induced by Brain-Derived Neurotrophic Factor (BDNF) is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. Molecular mechanisms of BDNF promoting cellular survival and synaptic plasticity have been intensely studied, yet its role in genome regulation is obscure. Here, through temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon BDNF treatment or depolarization (KCl), we identified BDNF-specific chromatin-to-gene expression programs. Our analyses revealed that enhancer activation is an early event in the regulatory control of BDNF treated neurons, where bZIP pioneered chromatin opening and co-regulatory transcription factors (Homeobox, EGRs, and CTCF) cooperate to induce fine-grained transcription. Deleting such cis-regulatory sequences decreased the BDNF mediated expression of Arc, a key regulator of synaptic plasticity. Furthermore, BDNF-induced accessible regions are linked to preferential exon usage of neurodevelopmental disorder related genes and heritability of neuronal complex traits. In conclusion, this work provides a comprehensive view of BDNF-mediated genome regulatory features and emphasizes the usage of genomic approaches on dissecting mammalian neuronal activity.
2022-09-01 | GSE166959 | GEO
Project description:Extracellular vesicles (EVs) are emerging as novel mediators of cellular communication, in part via the delivery of their contents including microRNAs; small non-coding RNAs that regulate gene expression and are crucial for neuronal circuit formation and function. Whether microRNAs are transferred between differentiated neurons is so far unknown. Moreover, the physiological role of EVs in inter-neuronal signaling is largely elusive. We observed that EVs derived from brain-derived neurotrophic factor (BDNF)-treated neurons induced dendrite complexity, synapse maturation and neuronal firing in recipient hippocampal neurons. This was dependent on the activity of three microRNAs, miR-132-5p, miR-218-5p and miR-690, that were specifically up-regulated in BDNF-induced EVs. Transcriptomic analysis further showed the differential expression of genes related to synaptogenesis in BDNF-EV-treated neurons, many of which are conserved targets of these miRNAs. Overall, this work demonstrates a novel mechanism of inter-neuronal communication, which may be highly relevant in neurological disorders characterized by aberrant BDNF signaling.
2023-12-05 | GSE184945 | GEO
Project description:Neuronal stimulation induced by the brain-derived neurotrophic factor (BDNF) triggers gene expression, which is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. However, its role in chromatin regulation is unclear. Here, using temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon either BDNF stimulation or depolarization (KCl), we identify features that define BDNF-specific chromatin-to-gene expression programs. Enhancer activation is an early event in the regulatory control of BDNF-treated neurons, where the bZIP motif-binding Fos protein pioneered chromatin opening and cooperated with co-regulatory transcription factors (Homeobox, EGRs, and CTCF) to induce transcription. Deleting cis-regulatory sequences affect BDNF-mediated Arc expression, a regulator of synaptic plasticity. BDNF-induced accessible regions are linked to preferential exon usage by neurodevelopmental disorder-related genes and the heritability of neuronal complex traits, which were validated in human iPSC-derived neurons. Thus, we provide a comprehensive view of BDNF-mediated genome regulatory features using comparative genomic approaches to dissect mammalian neuronal stimulation.
| S-EPMC9396287 | biostudies-literature
Project description:Brain-derived Neurotrophic Factor (BDNF) promotes neuronal differentiation and survival and is implicated in the pathogenesis of many neurological disorders. Here, we identified a novel intergenic enhancer located 170 kb from the Bdnf gene, which promotes the expression of Bdnf transcript variants during mouse neuronal differentiation and activity. Following Bdnf activation, enhancer-promoter contacts increase, and the region moves away from the repressive nuclear periphery. Bdnf enhancer activity is necessary for neuronal clustering and dendritogenesis in vitro, and for cortical development in vivo. Our findings provide the first evidence of a regulatory mechanism whereby the activation of a distal enhancer promotes Bdnf expression during brain development.
2023-01-04 | GSE190306 | GEO
Project description:Neuronal stimulation induced by the brain-derived neurotrophic factor (BDNF) triggers gene expression, which is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. However, its role in chromatin regulation is unclear. Here, using temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon either BDNF stimulation or depolarization (KCl), we identify features that define BDNF-specific chromatin-to-gene expression programs. Enhancer activation is an early event in the regulatory control of BDNF-treated neurons, where the bZIP motif-binding Fos protein pioneered chromatin opening and cooperated with co-regulatory transcription factors (Homeobox, EGRs, and CTCF) to induce transcription. Deleting cis-regulatory sequences affect BDNF-mediated Arc expression, a regulator of synaptic plasticity. BDNF-induced accessible regions are linked to preferential exon usage by neurodevelopmental disorder-related genes and the heritability of neuronal complex traits, which were validated in human iPSC-derived neurons. Thus, we provide a comprehensive view of BDNF-mediated genome regulatory features using comparative genomic approaches to dissect mammalian neuronal stimulation.
| S-SCDT-MSB-2021-10473 | biostudies-other
Project description:Brain region- and cell-specific transcriptome and epigenome molecular features are associated with heritability for neuropsychiatric traits. Here, we provide an atlas of chromatin accessibility and gene expression in neuronal and non-neuronal cells across 25 distinct regions across cortical and subcortical areas of the human brain from 6 neurotypical controls. We identified extensive gene expression and chromatin accessibility differences across brain regions. We further identified variation in alternative promoter-isoform usage and enhancer-promoter interactions across brain regions and found genes with distinct promoter-isoform usage are strongly enriched for neuropsychiatric risk variants. We identified brain region-specific chromatin co-accessibility and gene-coexpression modules that are robustly associated with genetic risk variants for neuropsychiatric disorders. Using an integrative approach, we identify a novel set of genes that is enriched for neuropsychiatric disorders risk variants but is independent of cell-type specific gene expression and annotated pathways. Our results provide a valuable multi-brain region molecular regulation resource and suggest a unique contribution of epigenetic modifications from the subcortical areas to neuropsychiatric disorders.
2022-08-25 | GSE211792 | GEO
Project description:Brain region- and cell-specific transcriptome and epigenome molecular features are associated with heritability for neuropsychiatric traits. Here, we provide an atlas of chromatin accessibility and gene expression in neuronal and non-neuronal cells across 25 distinct regions across cortical and subcortical areas of the human brain from 6 neurotypical controls. We identified extensive gene expression and chromatin accessibility differences across brain regions. We further identified variation in alternative promoter-isoform usage and enhancer-promoter interactions across brain regions and found genes with distinct promoter-isoform usage are strongly enriched for neuropsychiatric risk variants. We identified brain region-specific chromatin co-accessibility and gene-coexpression modules that are robustly associated with genetic risk variants for neuropsychiatric disorders. Using an integrative approach, we identify a novel set of genes that is enriched for neuropsychiatric disorders risk variants but is independent of cell-type specific gene expression and annotated pathways. Our results provide a valuable multi-brain region molecular regulation resource and suggest a unique contribution of epigenetic modifications from the subcortical areas to neuropsychiatric disorders.
2022-08-25 | GSE211822 | GEO
Project description:Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions selectively eliminate senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors as selectively capable of triggering apoptosis of senescent, but not proliferating, human fibroblasts. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF function supported an autocrine function for TrkB and BDNF, and the increased expression of BCL2L2 through ERK5, downstream of BDNF-TrkB, favored senescent cell survival. Strikingly, treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. Our results suggest that the SASP factor BDNF promotes cell survival by activating TrkB and is a promising therapeutic target to reduce the senescent cell burden.
2022-09-20 | GSE190998 | GEO
Project description:Regenerating new alveolar epithelium is essential for recovery from many lung diseases. This multi-cellular regenerative process occurs when type II alveolar pneumocytes (AT2), with support from mesenchymal niche cells, proliferate to generate more AT2 cells and transdifferentiate in type I pneumocytes. To elucidate how coordinated events between AT2 cells and mesenchyme restore alveolar epithelium we used unbiased genome-wide analysis of chromatin accessibility and gene expression in both cell types following acute lung injury. We observed that chromatin acessability in AT2 cells changes signficantly following acute lung injury. Newly accessible chromatin reveals new STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways in AT2 cells. Restoration of alveolar structures following both sterile and infectious lung injuries was inhibited when STAT3 signaling was lost in AT2 cells. Single-cell transcriptome analysis of regenerating AT2 cells identified brain neurotrophic factor (Bdnf) as the sole STAT3 target gene whose chromatin becomes newly accessible in a regenerating population of AT2 cells. BDNF increased alveolar organoid size and forming efficiency in murine and human models. The receptor for BDNF, TrkB, is uniquely? expressed on mesenchymal alveolar niche cells (MANC). Exposure of BDNF to TrkB increases expression of fibroblast growth factor 7 (Fgf7), an essential regenerative cytokine, in MANCs. Blocking Bdnf signaling with a TrkB receptor antagonist abrogated murine and human alveolar organoid formation. Finally, a small molecule TrkB agonist improved functional and histological outcomes in vivo following sterile and infectious lung injuries. Collectively, these data highlight the biological and therapeutic importance of the Stat3-Bdnf-TrkB axis in orchestrating alveolar epithelial regeneration
2020-06-01 | GSE132534 | GEO
Project description:Regenerating new alveolar epithelium is essential for recovery from many lung diseases. This multi-cellular regenerative process occurs when type II alveolar pneumocytes (AT2), with support from mesenchymal niche cells, proliferate to generate more AT2 cells and transdifferentiate in type I pneumocytes. To elucidate how coordinated events between AT2 cells and mesenchyme restore alveolar epithelium we used unbiased genome-wide analysis of chromatin accessibility and gene expression in both cell types following acute lung injury. We observed that chromatin acessability in AT2 cells changes signficantly following acute lung injury. Newly accessible chromatin reveals new STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways in AT2 cells. Restoration of alveolar structures following both sterile and infectious lung injuries was inhibited when STAT3 signaling was lost in AT2 cells. Single-cell transcriptome analysis of regenerating AT2 cells identified brain neurotrophic factor (Bdnf) as the sole STAT3 target gene whose chromatin becomes newly accessible in a regenerating population of AT2 cells. BDNF increased alveolar organoid size and forming efficiency in murine and human models. The receptor for BDNF, TrkB, is uniquely? expressed on mesenchymal alveolar niche cells (MANC). Exposure of BDNF to TrkB increases expression of fibroblast growth factor 7 (Fgf7), an essential regenerative cytokine, in MANCs. Blocking Bdnf signaling with a TrkB receptor antagonist abrogated murine and human alveolar organoid formation. Finally, a small molecule TrkB agonist improved functional and histological outcomes in vivo following sterile and infectious lung injuries. Collectively, these data highlight the biological and therapeutic importance of the Stat3-Bdnf-TrkB axis in orchestrating alveolar epithelial regeneration
2020-06-01 | GSE132533 | GEO