title: A transcription factor affinity-based code for mammalian transcription initiation.
abstract: 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 ( approximately 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 approximately 70% of mammalian microRNAs based on currently available data.
authors.affiliation: Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina 27708, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Megraw
authors.forename: Fernando
authors.initials: F
authors.lastname: Pereira
authors.forename: Shane T
authors.initials: ST
authors.lastname: Jensen
authors.forename: Uwe
authors.initials: U
authors.lastname: Ohler
authors.forename: Artemis G
authors.initials: AG
authors.lastname: Hatzigeorgiou
mesh_terms: D001482:Base Composition; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D030541:Databases, Genetic; D005786:Gene Expression Regulation / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000235:genetics; D016385:TATA Box / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
chemical_list: D014157:Transcription Factors; D004247:DNA; D012319:RNA Polymerase II