Open AccessThree-dimensional genome restructuring across timescales of activity-induced neuronal gene expression
Author(s) -
Jonathan A. Beagan,
Elissa D. Pastuzyn,
Lindsey R. Fernandez,
Michael H. Guo,
Kelly Feng,
Katelyn R. Titus,
Harshini Chandrashekar,
Jason D. Shepherd,
Jennifer E. Phillips-Cremins
Publication year - 2020
Publication title -
nature neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 13.403
H-Index - 422
eISSN - 1546-1726
pISSN - 1097-6256
DOI - 10.1038/s41593-020-0634-6
Subject(s) - chromatin , biology , enhancer , chromosome conformation capture , chromatin remodeling , gene , genetics , nucleosome , regulation of gene expression , neuroscience , microbiology and biotechnology , gene expression
Neuronal activation induces rapid transcription of immediate early genes (IEGs) and longer-term chromatin remodeling around secondary response genes (SRGs). Here, we use high-resolution chromosome-conformation-capture carbon-copy sequencing (5C-seq) to elucidate the extent to which long-range chromatin loops are altered during short- and long-term changes in neural activity. We find that more than 10% of loops surrounding select IEGs, SRGs, and synaptic genes are induced de novo during cortical neuron activation. IEGs Fos and Arc connect to activity-dependent enhancers via singular short-range loops that form within 20 min after stimulation, prior to peak messenger RNA levels. By contrast, the SRG Bdnf engages in both pre-existing and activity-inducible loops that form within 1-6 h. We also show that common single-nucleotide variants that are associated with autism and schizophrenia are colocalized with distinct classes of activity-dependent, looped enhancers. Our data link architectural complexity to transcriptional kinetics and reveal the rapid timescale by which higher-order chromatin architecture reconfigures during neuronal stimulation.