Chronic cocaine-regulated epigenome in mouse [RNA-Seq]

Increasing evidence supports a role for altered gene expression in mediating the lasting effects of cocaine on the brain, and recent work has demonstrated the involvement of chromatin modifications in these alterations. However, all such studies to date have been restricted by their reliance on microarray technologies which have intrinsic limitations. Here, we used advanced sequencing methods, RNA-seq and ChIP-seq, to obtain an unprecedented view of cocaine-induced changes in gene expression and associated adaptations in numerous modes of chromatin regulation in the nucleus accumbens, a key brain reward region. We identify unique combinations of chromatin changes, or signatures, that accompany cocaine’s regulation of gene expression, including the dramatic involvement of pre-mRNA alternative splicing in cocaine action. Together, this delineation of the cocaine-induced epigenome in the nucleus accumbens reveals several novel modes of drug regulation, thereby providing new insight into the biological basis of cocaine addiction. More broadly, the combinatorial chromatin and transcriptional approaches that we describe serve as an important resource for the field, as they can be applied to other systems to reveal novel transcriptional and epigenetic mechanisms of neuronal regulation. Overall design: Total RNA was isolated from mouse nucleus accumbens 24 hr after 7 day daily cocaine or saline control ip injection for mRNA sequencing by following illumina RNA seq kit protocol. Another batch of acute cocaine RNA-seq was performed using the same parameters except the treatment group was given 6 days of saline injection followed by 1 day of cocaine injection. The acute cocaine batch serves as control experiments.

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Feng J, Wilkinson M, Liu X, Purushothaman I, Ferguson D, Vialou V, Maze I, Shao N, Kennedy P, Koo J, Dias C, Laitman B, Stockman V, LaPlant Q, Cahill ME, Nestler EJ, Shen L