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Mammalian RNA polymerase II core promoters: insights from genome-wide studies

Key Points

  • Genome-wide methods have identified fivefold to tenfold more transcription start sites (TSSs) than were previously known to exist. Many of these occur at unexpected locations, such as assumed gene deserts, exons and 3′ UTRs of known genes.

  • Most promoters are not represented by the accepted model of a single TSS with an upstream TATA-box; a cluster of TSSs in a narrow region of genomic DNA is the most common pattern. Core promoters can be classified according to the distribution and relative usage of their TSSs.

  • The TSS distribution of core promoters is tightly coupled to the occurrence of both known cis-regulatory elements and gene function, and is generally conserved between humans and mice.

  • Few promoters use an extended initiator sequence to define the TSS. The most consistent pattern is a pyrimidine–purine dinucleotide that overlaps the TSS.

  • Most genes have at least two distinct promoters, which may be differentially regulated and generate mRNAs that encode different protein isoforms.

  • The wealth of TSS data enables new types of analysis, including the study of promoter evolution and functional analysis of promoters on a genome-wide scale.

Abstract

The identification and characterization of mammalian core promoters and transcription start sites is a prerequisite to understanding how RNA polymerase II transcription is controlled. New experimental technologies have enabled genome-wide discovery and characterization of core promoters, revealing that most mammalian genes do not conform to the simple model in which a TATA box directs transcription from a single defined nucleotide position. In fact, most genes have multiple promoters, within which there are multiple start sites, and alternative promoter usage generates diversity and complexity in the mammalian transcriptome and proteome. Promoters can be described by their start site usage distribution, which is coupled to the occurrence of cis-regulatory elements, gene function and evolutionary constraints. A comprehensive survey of mammalian promoters is a major step towards describing and understanding transcriptional control networks.

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Figure 1: TSS classes in mammalian promoters.
Figure 2: DNA motif predictions in core promoters depends on TSS architecture.
Figure 3: Complex TSS distributions within exons.

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Correspondence to David A. Hume.

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Database of Transcriptional Start Sites (DBTSS)

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Glossary

Transcription start site

A nucleotide in the genome that is the first to be transcribed into a particular RNA.

Core promoter

The genomic region that surrounds a TSS or cluster of TSSs. There is no absolute definition for the length of a core promoter; it is generally defined empirically as the segment of DNA that is required to recruit the transcription initiation complex and initiate transcription, given the appropriate external signals (such as enhancers).

Orthologues

Genes that originate from the same ancestral gene and are diverged by a speciation event.

Mediator complex

A multi-subunit complex that can respond to many different activators (such as DNA-bound transcription factors) and links such signals to the core promoter and the transcription machinery.

Tag library

A tag library is similar to a conventional cDNA library, except that, subsequently to isolation and cloning of the cDNA, small fragments are generated by restriction-enzyme cleavage, concatamerized and recloned. This approach enables efficient DNA sequencing of thousands of tags from a single library.

Tag cluster

This Review defines tag clusters as genomic regions in which two or more tags (of 20 nucleotides in length) overlap each other (both being mapped to the same strand).

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Sandelin, A., Carninci, P., Lenhard, B. et al. Mammalian RNA polymerase II core promoters: insights from genome-wide studies. Nat Rev Genet 8, 424–436 (2007). https://doi.org/10.1038/nrg2026

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