A code for transcription initiation in mammalian genomes

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Guarda la pagina tradotta: Un codice per l'inizio della trascrizione nei mammiferi

A code for transcription initiation in mammalian genomes

Martin C. Frith, Eivind Valen, Anders Krogh, Yoshihide Hayashizaki, Piero Carninci and Albin Sandelin


Genome-wide detection of transcription start sites (TSSs) has revealed that RNA Polymerase II transcription initiates at millions of positions in mammalian genomes. Most core promoters do not have a single TSS, but an array of closely located TSSs with different rates of initiation. As a rule, genes have more than one such core promoter; however, defining the boundaries between core promoters is not trivial. These discoveries prompt a re-evaluation of our models for transcription initiation. We describe a new framework for understanding the organization of transcription initiation. We show that initiation events are clustered on the chromosomes at multiple scales—clusters within clusters—indicating multiple regulatory processes. Within the smallest of such clusters, which can be interpreted as core promoters, the local DNA sequence predicts the relative transcription start usage of each nucleotide with a remarkable 91% accuracy, implying the existence of a DNA code that determines TSS selection. Conversely, the total expression strength of such clusters is only partially determined by the local DNA sequence. Thus, the overall control of transcription can be understood as a combination of large- and small-scale effects; the selection of transcription start sites is largely governed by the local DNA sequence, whereas the transcriptional activity of a locus is regulated at a different level; it is affected by distal features or events such as enhancers and chromatin remodeling.


  • Most of our knowledge of the transcription initiation process comes from detailed experiments on single-core promoters (for review, see Smale and Kadonaga 2003). As a consequence, the only reasonably detailed model of the process assumes that promoters have a TATA-box, which directs the positioning of the preinitiation complex—in effect initiating transcription from a single nucleotide (Hampsey 1998; Thomas and Chiang 2006). However, the fraction of promoters with clear TATA-boxes has been decreasing with the number of promoters discovered (Ohler et al. 2002; Gershenzon and Ioshikhes 2005; Molina and Grotewold 2005; Carninci et al. 2006; Cooper et al. 2006).
  • We have previously shown that broad TSS distributions are correlated with CpG islands and ubiquitously expressed genes, whereas promoters with a narrow TSS distribution frequently direct tissue-specific genes and often have a TATA box.

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