Enhancers, transcription factors and gene regulation in the vertebrate hypothalamus

DE SOUZA FS

Foz do Iguaçu, Brasil

Congreso; 23rd Congress of the International Union for Biochemistry and Molecular Biology. 44th Annual Meeting of the Brazilian Society for Biochemistry and Molecular Biology; 2015

IUBMB y SBBq

Gene expression depends crucially on cis-acting elements like promoters and distal enhancers, which act as binding platforms to specific combinations of transcription factors. In recent years, genome-wide studies have suggested that animal genomes possess hundreds of thousands of enhancers, and that one gene can be controlled simultaneously by two or more enhancers, suggesting that redundancy plays an important role in gene regulation. In this context, we have studied a pair of enhancers of the Proopiomelanocortin (Pomc) gene in vertebrates. Pomc encodes a prohormone expressed in the pituitary and the hypothalamus, where it plays important roles in controlling energy balance. Hypothalamic expression of Pomc is under the control of two enhancers ? named nPE1 and nPE2 - with seemingly identical transcriptional activities, suggesting redundancy. We have eliminated the enhancers in the mouse genome by targeted inactivation, and found that both are needed for full transcription of Pomc in hypothalamic neurons, although with different relative strenghts: while lack of nPE1 alone causes a visible overweight phenotype, an indication of Pomc defficiency, lack of nPE2 alone causes no visible physiological phenotype in mutant mice. The similar transcriptional activities of both enhancers suggest that both are controlled by similar transcription factors. Indeed, both enhancers harbour similar DNA motifs and bind to the LIM-homedomain transcription factor Islet1 (Isl1) in vitro and in vivo. Analysis of conditional mouse mutants for Isl1 shows that this factor is essential for Pomc expression in the hypothalamus. In summary, our results advance the understanding of regulatory redundancy, an emerging feature of animal genomes.