Epigenetic Readers of Lysine Acetylation Regulate Cocaine-Induced Plasticity

Abstract

Epigenetic processes that regulate histone acetylation play an essential role in behavioral and molecular responses to cocaine. To date, however, only a small fraction of the mechanisms involved in the addiction-associated acetylome have been investigated. Members of the bromodomain and extraterminal (BET) family of epigenetic "reader" proteins (BRD2, BRD3, BRD4, and BRDT) bind acetylated histones and serve as a scaffold for the recruitment of macromolecular complexes to modify chromatin accessibility and transcriptional activity. The role of BET proteins in cocaine-induced plasticity, however, remains elusive. Here, we used behavioral, pharmacological, and molecular techniques to examine the involvement of BET bromodomains in cocaine reward. Of the BET proteins, BRD4, but not BRD2 or BRD3, was significantly elevated in the nucleus accumbens (NAc) of mice and rats following repeated cocaine injections and selfadministration. Systemic and intra-accumbal inhibition of BRD4 with the BET inhibitor, JQ1, attenuated the rewarding effects of cocaine in a conditioned place preference procedure but did not affect conditioned place aversion, nor did JQ1 alone induce conditioned aversion or preference. Investigating the underlying mechanisms, we found that repeated cocaine injections enhanced the binding of BRD4, but not BRD3, to the promoter region of Bdnf in the NAc, whereas systemic injection of JQ1 attenuated cocaine-induced expression of Bdnf in the NAc. JQ1 and siRNA-mediated knockdown of BRD4 in vitro also reduced expression of Bdnf. These findings indicate that disrupting the interaction between BET proteins and their acetylated lysine substrates may provide a new therapeutic avenue for the treatment of drug addiction.

Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target

“…Recently, JQ1 has been shown to inhibit transcriptional responses that occur during memory formation (56), which might be important for mechanisms implicated in addiction and extinction learning. In addition, JQ1 attenuated the rewarding effect of cocaine in rats by interfering with drug-induced plasticity in the NAc (57). In the cocaine study, JQ1 was administered during the acquisition phase of conditioned place preference (57).…”

“…In addition, JQ1 attenuated the rewarding effect of cocaine in rats by interfering with drug-induced plasticity in the NAc (57). In the cocaine study, JQ1 was administered during the acquisition phase of conditioned place preference (57). Here, we show that bromodomain inhibitors effectively decrease drug self-administration behavior.…”

BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior

“…Recent data also suggest an underlying role of chromatin remodeling factors in the neurobiology of drug abuse. For example, chronic cocaine exposure results in increased expression of the bromodomain and extraterminal protein BRD4, an epigenetic reader protein (41), and PSMC5, an ATPase-containing subunit of the 19s proteasomal complex (42). We recently demonstrated that an accessory ATPase subunit of the ISWI family of chromatin remodeling complexes, bromodomain adjacent to zinc finger domain 1B, is also upregulated in the NAc (22).…”

Photoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degeneration

“…In fact, to the best of our knowledge, there is no publication reporting BET functions specifically in retinal degeneration. Two recent brain studies identified BET4-mediated transcriptional activation during memory formation [31] and cocaine-induced neuronal plasticity [32]. Another relevant study showed an inhibitory effect of JQ1 on human umbilical vein endothelial cell proliferation, migration, and tube formation [33].…”