Genetica Articles

REVIEWS
R E G U L AT O RY E L E M E N T S

Metazoan promoters: emerging characteristics and insights into transcriptional regulation
Boris Lenhard1,2, Albin Sandelin3 and Piero Carninci4

Abstract | Promoters are crucial for gene regulation. They vary greatly in terms of associated regulatory elements, sequence motifs, the choice of transcription start sites and other features. Severaltechnologies that harness next-generation sequencing have enabled recent advances in identifying promoters and their features, helping researchers who are investigating functional categories of promoters and their modes of regulation. Additional features of promoters that are being characterized include types of histone modifications, nucleosome positioning, RNA polymerase pausing and novel smallRNAs. In this Review, we discuss recent findings relating to metazoan promoters and how these findings are leading to a revised picture of what a gene promoter is and how it works.
Transcription start sites
(TSSs). Nucleotides in the genome that are the first to be transcribed into a particular RNA.

Institute of Clinical Sciences, Faculty of Medicine, Imperial College London; and MRC ClinicalSciences Centre, London, UK. 2 Department of Informatics, University of Bergen, Norway. 3 The Bioinformatics Center, Department of Biology and Biotech and Research Innovation Centre, University of Copenhagen, Denmark. 4 OMICS Science Center, RIKEN Yokohama Institute, Yokohama, Japan. e-mails: b.lenhard@imperial.ac.uk; albin@binf.ku.dk; carninci@riken.jp doi:10.1038/nrg3163 Published online 6 March2012
1

Gene promoters are the loci overlapping transcription start sites (TSSs), at which the total regulatory input of a gene is integrated into the rate of transcriptional initiation. The immediate role of the promoter is to bind and correctly position the transcription initiation complex, whose main catalytic activity consists of DNA-dependent RNA polymerase. In eukaryotes, RNA polymerase II(RNAPII)-transcribed genes are highly heterogeneous with respect to expression level and context specificity. Therefore, their transcriptional control needs to be highly specialized and dynamic; an important part of this diversity is mediated by different classes of RNAPII promoters, which differ dramatically in their architecture, which in turn determines the promoter function and regulationtype1,2. We focus here on functional diversity and cross-species equivalence of RNAPII promoters in Metazoa. Early models of promoters and transcription regulation in Metazoa have been inspired by promoter architectures of bacteria and single-cell eukaryotes. However, metazoan promoters are more complex: regulatory elements that control their activity can be spread over larger genomic space, and theirnumber of regulators is higher, reflecting additional and more challenging regulatory tasks faced by multicellular species, such as the development and maintenance of distinct tissues and cell–cell communication. In eukaryotes, the term ‘core promoter’ is often used to focus on the DNA region in the immediate vicinity of the TSS, which is assumed to dock the pre-initiation

(PIC). In thestandard view of RNAPII promoter function (FIG. 1a), the core promoter consists of several interchangeable sequence elements around the TSS, which bind core components of the PIC. The core elements (which are modelled as sequence motifs) in Metazoa have been extensively reviewed 1,3–7 and are summarized in FIG. 1b. Despite the similarity of their transcription initiation complexes, different metazoangroups have different key motifs associated with the ubiquitously expressed genes. These differences show that at least some of the motifs are lineage-specific innovations and are not an ancient delineator of promoter types. Alternatively, in some types of promoters, the motifs themselves might not be the major determinants of start site selection. In the classical model, the regulatory input to...