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A transcription factor affinity-based code for mammalian transcription initiation

Item Type:Article
Title:A transcription factor affinity-based code for mammalian transcription initiation
Creators Name:Megraw, M. and Pereira, F. and Jensen, S.T. and Ohler, U. and Hatzigeorgiou, A.G.
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.
Keywords:Base Composition, DNA, Gene Expression Regulation, Genetic Databases, Genetic Promoter Regions, Genetic Transcription, Human Genome, RNA Polymerase II, TATA Box, Transcription Factors, Transcription Initiation Site
Source:Genome Research
Publisher:Cold Spring Harbor Laboratory Press
Page Range:644-656
Date:April 2009
Official Publication:https://doi.org/10.1101/gr.085449.108
PubMed:View item in PubMed

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