CONICET | Buscador de Institutos y Recursos Humanos

Recently, it has been described that several genes in Drosophila melanogaster have more than one enhancer driving identical expression pattern during embryonic development. Such enhancers have been classified as "primary" (proximal) and "shadow" (distal) according to their relative position to the controlled gene. Recently, it has been proposed that such double enhancers might ensure robust developmental expression upon environmental and/or genetic disturbances. Although much has been learnt from studies in Drosophila, little is known about similar mechanisms in vertebrates. The proopiomelanocortin (Pomc) gene encodes a prohormone with essential functions in the response to stress and energy balance, being expressed in the pituitary and hypothalamus of vertebrates. We have found that neuronal expression of Pomc is controlled by two enhancers - dubbed nPE1 and nPE2 -, located 12 and 10 kb from the Pomc transcription start site, respectively. Using transgenic mice, we observed that both enhancers drive nearly identical expression patterns in the mammalian hypothalamus, starting at embryonic day 10.5, when endogenous Pomc expression commences. This overlapping enhancer activity is mantained throughout hypothalamic development and into adulthood. Both nPE1 and nPE2 are present in all placental mammals, indicating that such overlapping regulatory mechanism has been in place since about 130 million years ago. Thus, the case of the Pomc neuronal enhancers adds to a very short list of vertebrates genes with two regulatory regions displaying overlapping transcription activity during development and adulthood. Whether these enhancers also contribute to transcription robustness in mammals is subject of future work