Genome-wide identification and characterization of functional neuronal activity-dependent enhancers

Nat Neurosci. 2014 Oct;17(10):1330-9. doi: 10.1038/nn.3808. Epub 2014 Sep 7.


Experience-dependent gene transcription is required for nervous system development and function. However, the DNA regulatory elements that control this program of gene expression are not well defined. Here we characterize the enhancers that function across the genome to mediate activity-dependent transcription in mouse cortical neurons. We find that the subset of enhancers enriched for monomethylation of histone H3 Lys4 (H3K4me1) and binding of the transcriptional coactivator CREBBP (also called CBP) that shows increased acetylation of histone H3 Lys27 (H3K27ac) after membrane depolarization of cortical neurons functions to regulate activity-dependent transcription. A subset of these enhancers appears to require binding of FOS, which was previously thought to bind primarily to promoters. These findings suggest that FOS functions at enhancers to control activity-dependent gene programs that are critical for nervous system function and provide a resource of functional cis-regulatory elements that may give insight into the genetic variants that contribute to brain development and disease.

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

  • 2-Amino-5-phosphonovalerate / pharmacology
  • Animals
  • CREB-Binding Protein / metabolism
  • Embryo, Mammalian
  • Excitatory Amino Acid Antagonists / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Genome-Wide Association Study
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • MEF2 Transcription Factors / genetics
  • MEF2 Transcription Factors / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Neurons / drug effects
  • Neurons / physiology*
  • Oncogene Proteins v-fos / metabolism
  • Potassium Chloride / pharmacology
  • Sodium Channel Blockers / pharmacology
  • Tetrodotoxin / pharmacology
  • Time Factors
  • Visual Cortex / cytology


  • Excitatory Amino Acid Antagonists
  • MEF2 Transcription Factors
  • Oncogene Proteins v-fos
  • Sodium Channel Blockers
  • Tetrodotoxin
  • Potassium Chloride
  • 2-Amino-5-phosphonovalerate
  • Jumonji Domain-Containing Histone Demethylases
  • Kdm6b protein, mouse
  • CREB-Binding Protein
  • Crebbp protein, mouse

Associated data

  • GEO/GSE21161
  • GEO/GSE52386
  • GEO/GSE60049
  • GEO/GSE60192
  • GEO/GSM1264352
  • GEO/GSM1264354
  • GEO/GSM1264356
  • GEO/GSM1264358
  • GEO/GSM1264360
  • GEO/GSM1264362
  • GEO/GSM1264364
  • GEO/GSM1264366
  • GEO/GSM1264368