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

Abstract

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 distally. 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 enhancers. This is conceivable, as various core promoter sequence elements are differentially distributed between genes of different functions, including elements that are predominantly found at either developmentally regulated or at housekeeping genes. 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.

Enhancers, enhancers – from their discovery to today’s universe of transcription enhancers

“…How does each enhancer find its target? Proximity to one vs. anther promoter helps, but there are numerous exceptions, and open questions remain in spite of recent progress such as the finding that Drosophila 'housekeeping' genes specifically interact with an enhancer class of their own (Zabidi et al, 2014). One also may wonder, why remote control?…”

Promoter architectures and developmental gene regulation

“…For instance, it was shown that the presence of specific core promoter elements in Drosophila makes promoters responsive to distinct enhancers [119]. A recent functional study of enhancer activity genome-wide revealed specificity of enhancers towards either housekeeping or developmental core promoters that differ in their core promoter elements, separating two major transcriptional programs in Drosophila [14].…”

“…Interestingly, the distinct promoter classes were recently shown to respond to regulation by different sets of distal-acting enhancers, separating the housekeeping and developmental transcriptional programs in Drosophila [14] and emphasizing the importance of core promoters in transcriptional regulation during development.…”

“…They receive and integrate various regulatory inputs and convert them into precise rate of transcription initiation. Core promoter elements can determine the responsiveness of the promoter to transcriptional regulation by cis-regulatory elements and trans-acting factors in multicellular organisms [13,14], and are major determinants of gene expression level in yeast [15], making them central, active components of transcriptional regulation.…”

Core promoters across the genome

“…They have multiple, functionally distinct 1 and sometimes physically overlapping 2 architectures, which determine their responsiveness to long-range regulation and to developmental and differentiation regulatory programs (reviewed in ref. 3).…”