RT Journal
A1 Megraw, Molly
A1 Pereira, Fernando
A1 Jensen, Shane T.
A1 Ohler, Uwe
A1 Hatzigeorgiou, Artemis G.
T1 A transcription factor affinity-based code for mammalian transcription initiation
JF Genome Research 
JO Genome Research 
YR 2009 
FD April 01 
VO 19 
IS 4 
SP 644 
OP 656 
DO 10.1101/gr.085449.108 
UL http://genome.cshlp.org/content/19/4/644.abstract 
AB The recent arrival of large-scale cap analysis of gene expression (CAGE) data sets in mammals provides a wealth of quantitative information on coding and noncoding RNA polymerase II transcription start sites (TSS). Genome-wide CAGE studies reveal that a large fraction of TSS exhibit peaks where the vast majority of associated tags map to a particular location (∼45%), whereas other active regions contain a broader distribution of initiation events. The presence of a strong single peak suggests that transcription at these locations may be mediated by position-specific sequence features. We therefore propose a new model for single-peaked TSS based solely on known transcription factors (TFs) and their respective regions of positional enrichment. This probabilistic model leads to near-perfect classification results in cross-validation (auROC = 0.98), and performance in genomic scans demonstrates that TSS prediction with both high accuracy and spatial resolution is achievable for a specific but large subgroup of mammalian promoters. The interpretable model structure suggests a DNA code in which canonical sequence features such as TATA-box, Initiator, and GC content do play a significant role, but many additional TFs show distinct spatial biases with respect to TSS location and are important contributors to the accurate prediction of single-peak transcription initiation sites. The model structure also reveals that CAGE tag clusters distal from annotated gene starts have distinct characteristics compared to those close to gene 5′-ends. Using this high-resolution single-peak model, we predict TSS for ∼70% of mammalian microRNAs based on currently available data.