Partially Redundant Enhancers Cooperatively Maintain Mammalian Expression Above a Critical Functional Threshold

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The stability of animal form and function in the face of genetic and environmental variation relies on consistent gene expression. Multiple enhancers, each specifying a unique regulatory domain, control the precise spatiotemporal expression of many genes. However, in some genes apparently redundant enhancers regulate expression in overlapping cell-specific patterns. Although this arrangement has been shown to be important for developmental robustness in invertebrates, the role of apparently redundant enhancers in vertebrate species and in genes functioning in adulthood is poorly understood. Here, we show that expression of the mammalian Pomc gene is controlled in a tissue-specific manner by two such apparently redundant enhancers. We used targeted deletion of the individual enhancers to delineate their respective contributions to Pomc expression in the brain. Since Pomc expression from its intact locus exceeds the sum of the individual enhancer contributions to Pomc mRNA levels in embryonic mice, we infer a synergistic action between the enhancers during development. In contrast, the interaction between the enhancers is additive in adult mice. Deletion of both enhancers simultaneously almost completely abolished Pomc expression and the mutant mice displayed extreme obesity and metabolic dysfunction, while deletion of the individual enhancers had a modest or no phenotypic effect. Together, our results demonstrate that the two enhancers cooperatively maintain Pomc expression above a critical functional threshold.

Vyšlo v časopise: Partially Redundant Enhancers Cooperatively Maintain Mammalian Expression Above a Critical Functional Threshold. PLoS Genet 11(2): e32767. doi:10.1371/journal.pgen.1004935
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004935

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