BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice

Nat Neurosci. 2015 Oct;18(10):1464-73. doi: 10.1038/nn.4095. Epub 2015 Aug 24.


Precise regulation of transcription is crucial for the cellular mechanisms underlying memory formation. However, the link between neuronal stimulation and the proteins that directly interact with histone modifications to activate transcription in neurons remains unclear. Brd4 is a member of the bromodomain and extra-terminal domain (BET) protein family, which binds acetylated histones and is a critical regulator of transcription in many cell types, including transcription in response to external cues. Small molecule BET inhibitors are in clinical trials, yet almost nothing is known about Brd4 function in the brain. Here we show that Brd4 mediates the transcriptional regulation underlying learning and memory. The loss of Brd4 function affects critical synaptic proteins, which results in memory deficits in mice but also decreases seizure susceptibility. Thus Brd4 provides a critical link between neuronal activation and the transcriptional responses that occur during memory formation.

Publication types

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

MeSH terms

  • Animals
  • Azepines / pharmacology
  • Blotting, Western
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Female
  • Immunohistochemistry
  • Male
  • Memory / drug effects
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Neurons / drug effects
  • Neurons / metabolism*
  • Nuclear Proteins / metabolism*
  • Polymerase Chain Reaction
  • RNA, Small Interfering
  • Seizures
  • Transcription Factors / metabolism*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology*
  • Transfection
  • Triazoles / pharmacology


  • (+)-JQ1 compound
  • Azepines
  • Brd4 protein, mouse
  • Nuclear Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • Triazoles

Associated data

  • GEO/GSE63809