Journal
NATURE NEUROSCIENCE
Volume 23, Issue 6, Pages 707-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41593-020-0634-6
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Funding
- New York Stem Cell Foundation
- US National Institutes of Health (NIH) Director's New Innovator Award from the National Institute of Mental Health [1DP2MH11024701]
- National Institute of Mental Health [R01MH112766]
- Zuckerberg Ben Barres Early Career Acceleration Award
- 4D Nucleome Common Fund [1U01HL12999801]
- NSF-NIGMS [1562665]
- Brain Research Foundation Fay Frank Seed Grant
- National Institute of Neurological Disorders and Stroke grant [R01NS114226]
- National Science Foundation Graduate Research Fellowships [DGE-1321851]
- Division Of Mathematical Sciences
- Direct For Mathematical & Physical Scien [1562665] Funding Source: National Science Foundation
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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. This study elucidates how long-range chromatin loops are altered during short- and long-term changes in neural activity, and analyzes the interplay between the 3D genome and the linear epigenome during activity-dependent transcriptional responses.
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