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

Nature Neuroscience volume 18, pages 14641473 (2015) | Download Citation

Abstract

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.

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Acknowledgements

We thank K. Ozato for the Brd4 construct, J. Gresack and the Rockefeller behavioral core for guidance and suggestions, K. Thomas for microscopy expertise, the Memorial Sloan-Kettering Cancer Center histology core for immunohistochemistry support, A. Soshnev for the schematic model graphic, J. Gerace for editing and members of the Allis laboratory for feedback. Support for this work was provided by a grant from the Robertson Foundation, a Ruth Kirschstein US National Research Service Award fellowship (F32MH103921), the US National Institutes of Health (R01 NS34389, NS081706) and a Simons Foundation Research Award. R.B.D. is an Investigator of the Howard Hughes Medical Institute.

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Affiliations

  1. Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York, USA.

    • Erica Korb
    •  & C David Allis
  2. Laboratory of Molecular Neuro-oncology, The Rockefeller University, New York, New York, USA.

    • Margo Herre
    • , Ilana Zucker-Scharff
    •  & Robert B Darnell

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Contributions

E.K. wrote the manuscript and designed and carried out experiments. M.H. helped carry out behavioral testing and molecular studies. I.Z.-S. helped with seizure testing. R.B.D. helped initiate and design the project and provided feedback, and C.D.A. provided support, feedback and guidance.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Erica Korb or C David Allis.

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DOI

https://doi.org/10.1038/nn.4095