Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala; implications for obesity, depression and alcoholism.
Résumé
Abstract; The precise expression of the galanin gene (GAL) in the paraventricular nucleus (PVN) and in the amygdala of higher vertebrates suggests the involvement of highly conserved but as yet unidentified regulatory sequences that are critical to allow the galanin gene to control alcohol and fat intake and modulate mood. We used comparative genomics to identify a remote and highly conserved sequence that lay 42kb 5' of the human GAL transcriptional start site that we called GAL5.1. GAL5.1 activated promoter activity in neurones of the PVN, arcuate nucleus and amygdala that also expressed the galanin peptide. Analysis in SHSY-5Y neuroblastoma cells demonstrated that GAL5.1 acted as an enhancer of promoter activity after PKC activation. GAL5.1 contained two polymorphisms; rs2513280(C/G) and rs2513281(A/G), that only occurred in two allelic combinations (GG or CA) where the dominant GG alelle occurred in 70-83% of the human population. Recreation of these alleles in reporter constructs and subsequent magnetofection into primary rat hypothalamic neurones showed that the CA allele was 40% less active than the GG allele. Based on these observations, and considering the known roles of galanin in modulating alcohol and fat intake, we propose the hypothesis that the weaker CA allele may affect food and alcohol intake preference. Further analysis of this novel polymorphic enhancer may allow us to understand how allele specific differences in the regulation of the GAL gene may play a role in alcoholism, depression and obesity.
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