The transcription factor ΔFosB has been proposed as a molecular switch for the transition from casual, volitional drug use into a chronically addicted state, but the upstream regulatory mechanisms governing ΔFosB expression are incompletely understood. In this study, we find a novel regulatory role for the transcription factor E2F3, recently implicated in transcriptional regulation by cocaine, in controlling ΔFosB induction in the mouse nucleus accumbens (NAc) following cocaine administration. We find that an E2F consensus sequence 500 bp upstream of the Fosb transcription start site is enriched for E2F3 specifically over other E2F isoforms. We further conclude that ΔFosB expression is regulated specifically by E2F3a, not E2F3b, that E2f3a expression is specific to D1 receptor-expressing medium spiny neurons, and that E2F3a overexpression in NAc recapitulates the induction of Fosb and ΔFosb mRNA expression observed after chronic cocaine exposure. E2F3a knockdown in NAc does not abolish ΔFosb induction by cocaine, a result consistent with previously published data showing that singular knockdown of upstream regulators of ΔFosB is insufficient to block cocaine-induced expression. Finally, to elucidate potential combinatorial epigenetic mechanisms involved in E2F3a’s regulation of Fosb, we explore H3K4me3 enrichment at the Fosb promoter and find that it is not enhanced by E2F3a overexpression, suggesting that it may instead be a pre-existing permissive mark allowing for E2F3a to interact with Fosb. Together, these findings support a role for E2F3a as a novel, upstream regulator of the addiction-mediating transcription factor ΔFosB in NAc.
- Fosb induction in nucleus accumbens by cocaine is regulated by e2f3a
- H.M. Cates - Icahn School of Medicine at Mount SinaiC.K. Lardner - Icahn School of Medicine at Mount SinaiR.C. Bagot - Icahn School of Medicine at Mount SinaiR.L. Neve - Massachusetts General HospitalE.J. Nestler - Icahn School of Medicine at Mount Sinai
- ENeuro, Vol.6(2)
- Adelphi University; Biology; College of Arts and Sciences
- Journal article
- https://doi.org/10.1523/ENEURO.0325-18.2019
- 991004357998106266