한빛사논문
Ignacio L Ibarra1,2,3,†, Vikram S Ratnu4,†, Lucia Gordillo2,4,†, In-Young Hwang1,4, Luca Mariani5, Kathryn Weinand5, Henrik M Hammarén1,4, Jennifer Heck4, Martha L Bulyk5,6, Mikhail M Savitski4, Judith B Zaugg *,1 and Kyung-Min Noh *,4
1Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
2Faculty of Biosciences, Collaboration for Joint PhD Degree between EMBL and Heidelberg University, Heidelberg, Germany
3Institute of Computational Biology, Helmholtz Center Munich, Oberschleißheim, Germany
4Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
5Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
6Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
† These authors contributed equally to this work
*Corresponding Author: Judith B Zaugg, Kyung-Min Noh
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.
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