Genome-wide profiling identifies a subset of methamphetamine (METH)-induced genes associated with METH-induced increased H4K5Ac binding in the rat striatum.
BACKGROUND
METH is an illicit drug of abuse that influences gene expression in the rat striatum. Histone modifications regulate gene transcription.


METHODS
We therefore used microarray analysis and genome-scale approaches to examine potential relationships between the effects of METH on gene expression and on DNA binding of histone H4 acetylated at lysine 4 (H4K5Ac) in the rat dorsal striatum of METH-naïve and METH-pretreated rats.


RESULTS
Acute and chronic METH administration caused differential changes in striatal gene expression. METH also increased H4K5Ac binding around the transcriptional start sites (TSSs) of genes in the rat striatum. In order to relate gene expression to histone acetylation, we binned genes of similar expression into groups of 100 genes and proceeded to relate gene expression to H4K5Ac binding. We found a positive correlation between gene expression and H4K5Ac binding in the striatum of control rats. Similar correlations were observed in METH-treated rats. Genes that showed acute METH-induced increased expression in saline-pretreated rats also showed METH-induced increased H4K5Ac binding. The acute METH injection caused similar increases in H4K5Ac binding in METH-pretreated rats, without affecting gene expression to the same degree. Finally, genes that showed METH-induced decreased expression exhibited either decreases or no changes in H4K5Ac binding.


CONCLUSIONS
Acute METH injections caused increased gene expression of genes that showed increased H4K5Ac binding near their transcription start sites.
Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD 21224, USA. jcadet@intra.nida.nih.gov
Jean Lud
JL
Cadet
Subramaniam
S
Jayanthi
Michael T
MT
McCoy
Bruce
B
Ladenheim
Fabienne
F
Saint-Preux
Elin
E
Lehrmann
Supriyo
S
De
Kevin G
KG
Becker
Christie
C
Brannock
D000107:Acetylation; D000818:Animals; D047369:Chromatin Immunoprecipitation; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006657:Histones / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic
D003598:Cytoskeletal Proteins; D006657:Histones; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; C092069:activity regulated cytoskeletal-associated protein; D008694:Methamphetamine