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Enhancer–core-promoter specificity separates developmental and housekeeping gene regulation

2014; Nature Portfolio; Volume: 518; Issue: 7540 Linguagem: Inglês

10.1038/nature13994

1476-4687

Muhammad A. Zabidi, Cosmas D. Arnold, Katharina Schernhuber, Michaela Pagani, Martina Rath, Olga Frank, Alexander Stark,

RNA Research and Splicing

The core promoters of developmental and housekeeping genes are shown to have distinct specificities for different enhancer sequences in Drosophila, and this specificity separates developmental and housekeeping gene regulatory programs across the genome. The transcription of genes during development involves interactions between RNA polymerase II bound to core promoters, and factors bound to distal enhancers that confer cell-type-specific activation. Alexander Stark and colleagues show in Drosophila that the enhancers of developmental and housekeeping genes have distinct specificities for different core promoter sequences, and that this sequence-encoded enhancer–core-promoter specificity separates developmental and housekeeping gene regulatory programs across the genome. Gene transcription in animals involves the assembly of RNA polymerase II at core promoters and its cell-type-specific activation by enhancers that can be located more distally1. However, how ubiquitous expression of housekeeping genes is achieved has been less clear. In particular, it is unknown whether ubiquitously active enhancers exist and how developmental and housekeeping gene regulation is separated. An attractive hypothesis is that different core promoters might exhibit an intrinsic specificity to certain enhancers2,3,4,5,6. This is conceivable, as various core promoter sequence elements are differentially distributed between genes of different functions7, including elements that are predominantly found at either developmentally regulated or at housekeeping genes8,9,10. Here we show that thousands of enhancers in Drosophila melanogaster S2 and ovarian somatic cells (OSCs) exhibit a marked specificity to one of two core promoters—one derived from a ubiquitously expressed ribosomal protein gene and another from a developmentally regulated transcription factor—and confirm the existence of these two classes for five additional core promoters from genes with diverse functions. Housekeeping enhancers are active across the two cell types, while developmental enhancers exhibit strong cell-type specificity. Both enhancer classes differ in their genomic distribution, the functions of neighbouring genes, and the core promoter elements of these neighbouring genes. In addition, we identify two transcription factors—Dref and Trl—that bind and activate housekeeping versus developmental enhancers, respectively. Our results provide evidence for a sequence-encoded enhancer–core-promoter specificity that separates developmental and housekeeping gene regulatory programs for thousands of enhancers and their target genes across the entire genome.