Enhancement of BDNF expression and memory by HDAC inhibition requires BET bromodomain reader proteins

Gregory C. Sartor, Andrea M. Malvezzi, Ashok Kumar, Nadja S. Andrade, Hannah J. Wiedner, Samantha J. Vilca, Karolina J. Janczura, Amir Bagheri, Hassan Al-Ali, Samuel K. Powell, Peyton T. Brown, Claude H. Volmar, Thomas C. Foster, Zane Zeier, Claes Wahlestedt

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Histone deacetylase (HDAC) inhibitors may have therapeutic utility in multiple neurological and psychiatric disorders, but the underlying mechanisms remain unclear. Here, we identify BRD4, a BET bromodomain reader of acetyl-lysine histones, as an essential component involved in potentiated expression of brain-derived neurotrophic factor (BDNF) and memory following HDAC inhibition. In in vitro studies, we reveal that pharmacological inhibition of BRD4 reversed the increase in BDNF mRNA induced by the class I/IIb HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Knock-down of HDAC2 and HDAC3, but not other HDACs, increased BDNF mRNA expression, whereas knock-down of BRD4 blocked these effects. Using dCas9-BRD4, locus-specific targeting of BRD4 to the BDNF promoter increased BDNF mRNA. In additional studies, RGFP966, a pharmacological inhibitor of HDAC3, elevated BDNF expression and BRD4 binding to the BDNF promoter, effects that were abrogated by JQ1 (an inhibitor of BRD4). Examining known epigenetic targets of BRD4 and HDAC3, we show that H4K5ac and H4K8ac modifications and H4K5ac enrichment at the BDNF promoter were elevated following RGFP966 treatment. In electrophysiological studies, JQ1 reversed RGFP966-induced enhancement of LTP in hippocampal slice preparations. Last, in behavioral studies, RGFP966 increased subthreshold novel object recognition memory and cocaine place preference in male C57BL/6 mice, effects that were reversed by cotreatment with JQ1. Together, these data reveal that BRD4 plays a key role in HDAC3 inhibitor-induced potentiation of BDNF expression, neuroplasticity, and memory.

Original languageEnglish (US)
Pages (from-to)612-626
Number of pages15
JournalJournal of Neuroscience
Volume39
Issue number4
DOIs
StatePublished - Jan 23 2019

Keywords

  • BDNF
  • BET
  • BRD4
  • Bromodomain
  • HDAC3
  • JQ1

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Enhancement of BDNF expression and memory by HDAC inhibition requires BET bromodomain reader proteins'. Together they form a unique fingerprint.

  • Cite this

    Sartor, G. C., Malvezzi, A. M., Kumar, A., Andrade, N. S., Wiedner, H. J., Vilca, S. J., Janczura, K. J., Bagheri, A., Al-Ali, H., Powell, S. K., Brown, P. T., Volmar, C. H., Foster, T. C., Zeier, Z., & Wahlestedt, C. (2019). Enhancement of BDNF expression and memory by HDAC inhibition requires BET bromodomain reader proteins. Journal of Neuroscience, 39(4), 612-626. https://doi.org/10.1523/JNEUROSCI.1604-18.2018