Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements.

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. Synopsis: Dynamic multi‐omic profiling and comparative genomics are used to dissect the role of BDNF on neuronal chromatin. A comprehensive description of BDNF‐specific regulatory features is provided, from transcription factor interactions to complex traits.Comparative profiling of mouse neuron stimulation with BDNF or KCl using ATAC‐, RNA‐seq, and proteomics reveals BDNF‐specific gene expression regulatory features.Early enhancer activation is a signature feature of BDNF stimulation that coordinates the transcriptional response, whereas KCl stimulation directly affects promoters with a delayed effect on transcription.BDNF‐responsive chromatin regions conserved between mouse and human display shared neuropsychiatric complex trait associations. [ABSTRACT FROM AUTHOR]