Genome-wide analysis of acetylated H4K5 binding offers new insights into the acute and chronic effects of METH on gene expression in the dorsal striatum

ABSTRACT: In contrast to the acute METH-induced transcriptional changes, chronic METH administration produces differential changes in IEG responses and blunts the striatal effects of a single METH injection (McCoy et al., 2011). These observations suggested that chromic METH might have caused changes in the molecular machinery that controls the acute effects of the drug. Gene transcription is regulated by complex interactions of transcription factors with regulatory elements [14,15]. During resting states, DNA is compacted in a way that interferes with the binding of transcription factors whereas DNA becomes more accessible during activation of cells by various stimuli [16]. DNA is indeed packaged into chromatin whose fundamental subunit, the nucleosome, is made of 4 core histones, histones H2A, H2B, H3, and H4 that form an octomer (2 of each histone) surrounded by 146 bp of DNA [17]. The N-tails of histones possess lysine residues that can be reversibly acetylated or deacetylated by several histone acetyltransferases (HATs) or by histone deacetylases (HDACs), respectively [18,19]. These changes promote alterations in gene expression by modifying chromatin conformation and enabling or inhibiting recruitment of regulatory factors onto DNA sequences [20]. Herein, we report that the acute, but not the chronic, transcriptional effects of METH are mediated, for the most part, by increased DNA binding of histone H4 acetylated at lysine 5 (H4K5ac). These results suggest that other factors, including histone and/or DNA methylation, might play a more important role in mediating the molecular effects of chronic METH exposure.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE42776 | GEO | 2013/02/28

SECONDARY ACCESSION(S): PRJNA183116

REPOSITORIES: GEO