Epigenetic control of GLT-1 gene activity and its modulation by psychoactive drugs in comparison to genome-wide drug effects

Astrocytic lineage commitment and brain region-dependentspecialization of glia are partly ascribed to epigenetic proc-esses. Clearance of glutamate is an essential task, whichastrocytes assume in a temporal-spatial fashion by distinctglutamate transporter expression. Glutamate transportersubtype 1 (GLT-1) is predominant in cortex (CTX), while itplays an inferior role in cerebellum (CER). Here, we set outto identify regulatory elements that could account for the dif-ferences in brain region-specific activity as well as responseto dexamethasone (DEX) or epigenetic factors. We found adistal promoter element at the shore of the CpG islandexhibiting enhancer function in response to DEX in reportergene assays. This shore region showed slight enrichmentin repressive trimethyl-histone H3 (Lys27) and under-representation of acetyl-histone H4 (H4ac) marks in DEXnonresponsive CER astrocytes as determined by chromatinimmunoprecipitation. In addition, CpG sites of the shoreregion displayed higher methylation in CER than in CTXcells. Targeted in vitro methylation of CpG sites within theshore abrogated the stimulatory effects of DEX. Interest-ingly, the shore was characterized by a pronounced epige-netic plasticity in CTX cells since DEX exposure elicited anincrease of H4ac in CTX in comparison to DEX nonrespon-sive CER. The transcriptional activity of this region was alsoaffected by histone deacetylase inhibitors in a methylation-and brain region-dependent manner. Together, our studyhighlights the impact of an epigenetically adaptive DNA ele-ment of the GLT-1 promoter being decisive for brain region-specific activity and reactivity. VC2012 Wiley Periodicals, Inc.