Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements
Abstract 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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-08-01
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| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/msb.202110473 |
| _version_ | 1797281045014380544 |
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| author | Ignacio L Ibarra Vikram S Ratnu Lucia Gordillo In‐Young Hwang Luca Mariani Kathryn Weinand Henrik M Hammarén Jennifer Heck Martha L Bulyk Mikhail M Savitski Judith B Zaugg Kyung‐Min Noh |
| author_facet | Ignacio L Ibarra Vikram S Ratnu Lucia Gordillo In‐Young Hwang Luca Mariani Kathryn Weinand Henrik M Hammarén Jennifer Heck Martha L Bulyk Mikhail M Savitski Judith B Zaugg Kyung‐Min Noh |
| author_sort | Ignacio L Ibarra |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-07T16:50:53Z |
| format | Article |
| id | doaj.art-3980541312b745348c31389d5c19f1aa |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2024-03-07T16:50:53Z |
| publishDate | 2022-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-3980541312b745348c31389d5c19f1aa2024-03-03T05:21:53ZengSpringer NatureMolecular Systems Biology1744-42922022-08-01188n/an/a10.15252/msb.202110473Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elementsIgnacio L Ibarra0Vikram S Ratnu1Lucia Gordillo2In‐Young Hwang3Luca Mariani4Kathryn Weinand5Henrik M Hammarén6Jennifer Heck7Martha L Bulyk8Mikhail M Savitski9Judith B Zaugg10Kyung‐Min Noh11Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL) Heidelberg GermanyGenome Biology Unit European Molecular Biology Laboratory (EMBL) Heidelberg GermanyFaculty of Biosciences Collaboration for Joint PhD Degree between EMBL and Heidelberg University Heidelberg GermanyStructural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL) Heidelberg GermanyDivision of Genetics, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USADivision of Genetics, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USAStructural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL) Heidelberg GermanyGenome Biology Unit European Molecular Biology Laboratory (EMBL) Heidelberg GermanyDivision of Genetics, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USAGenome Biology Unit European Molecular Biology Laboratory (EMBL) Heidelberg GermanyStructural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL) Heidelberg GermanyGenome Biology Unit European Molecular Biology Laboratory (EMBL) Heidelberg GermanyAbstract 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.https://doi.org/10.15252/msb.202110473enhancersgene expressionneuronal stimulationpost‐mitotic neuronstranscription factors |
| spellingShingle | Ignacio L Ibarra Vikram S Ratnu Lucia Gordillo In‐Young Hwang Luca Mariani Kathryn Weinand Henrik M Hammarén Jennifer Heck Martha L Bulyk Mikhail M Savitski Judith B Zaugg Kyung‐Min Noh Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements Molecular Systems Biology enhancers gene expression neuronal stimulation post‐mitotic neurons transcription factors |
| title | Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements |
| title_full | Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements |
| title_fullStr | Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements |
| title_full_unstemmed | Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements |
| title_short | Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements |
| title_sort | comparative chromatin accessibility upon bdnf stimulation delineates neuronal regulatory elements |
| topic | enhancers gene expression neuronal stimulation post‐mitotic neurons transcription factors |
| url | https://doi.org/10.15252/msb.202110473 |
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