Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression

Nat Neurosci. 2020 Jun;23(6):707-717. doi: 10.1038/s41593-020-0634-6. Epub 2020 May 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bicuculline / pharmacology
  • Brain-Derived Neurotrophic Factor / physiology
  • Chromatin Assembly and Disassembly / genetics
  • Chromatin Assembly and Disassembly / physiology*
  • Cytoskeletal Proteins / physiology
  • Gene Expression / physiology*
  • Genome / drug effects
  • Genome / genetics*
  • Humans
  • Mice
  • Nerve Tissue Proteins / physiology
  • Neurons / drug effects
  • Neurons / physiology*
  • Proto-Oncogene Proteins c-fos / physiology
  • Tetrodotoxin / pharmacology
  • Time Factors


  • Brain-Derived Neurotrophic Factor
  • Cytoskeletal Proteins
  • Fos protein, mouse
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-fos
  • activity regulated cytoskeletal-associated protein
  • Tetrodotoxin
  • Bicuculline