Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements.

Autor: Ibarra IL; Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Faculty of Biosciences, Collaboration for Joint PhD Degree between EMBL and Heidelberg University, Heidelberg, Germany.; Institute of Computational Biology, Helmholtz Center Munich, Oberschleißheim, Germany., Ratnu VS; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Gordillo L; Faculty of Biosciences, Collaboration for Joint PhD Degree between EMBL and Heidelberg University, Heidelberg, Germany.; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Hwang IY; Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Mariani L; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Weinand K; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Hammarén HM; Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Heck J; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Bulyk ML; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Savitski MM; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Zaugg JB; Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Noh KM; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Jazyk: angličtina
Zdroj: Molecular systems biology [Mol Syst Biol] 2022 Aug; Vol. 18 (8), pp. e10473.
DOI: 10.15252/msb.202110473
Abstrakt: 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.
(© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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