CELL-TYPE-SPECIFIC REGULATION OF CHOLINE-ACETYLTRANSFERASE GENE-EXPRESSION - ROLE OF THE NEURON-RESTRICTIVE SILENCER ELEMENT AND CHOLINERGIC-SPECIFIC ENHANCER SEQUENCES

This study demonstrates the presence of positive and negative regulato ry elements within a 2336-base pair-long region of the rat choline ace tyltransferase (ChAT) gene promoter that cooperate to direct cell type -specific expression in cholinergic cells, A 21-base pair-long neuron- restrictive silencer element (NRSE) was identified in the proximal par t of this region, This element was recognized by the neuron-restrictiv e silencer factor (NRSF), previously shown to regulate expression of o ther neuron-specific genes, The ChAT NRSE was inactive in both choline rgic and non-cholinergic neuronal cells, but repressed expression from a heterologous promoter in non-neuronal cells, Specific deletion of t his element allowed ChAT gene promoter activity in non-neuronal cells, and overexpression of NRSF repressed ChAT gene promoter activity in c holinergic cells, The distal part of the ChAT gene promoter showed cho linergic-specific enhancing activity, which stimulated promoter activi ty in cholinergic cells, but was inactive in non-cholinergic neuronal and non-neuronal cells, This enhancer region suppressed the activity o f the ChAT NRSE in cholinergic cells, even after NRSF overexpression, Thus, at least two kinds of regulatory elements cooperate to direct Ch AT gene expression to cholinergic neurons, namely a neuron-restrictive silencer element and a cholinergic-specific enhancer.