Abstract
Chromatin accessibility is essential for transcriptional activation of genomic regions. It is well established that transcription factors (TFs) and histone modifications (HMs) play critical roles in chromatin accessibility regulation. However, there is a lack of studies that quantify these relationships. Here we constructed a two-layer model to predict chromatin accessibility by integrating DNA sequence, TF binding, and HM signals. By applying the model to two human cell lines (GM12878 and HepG2), we found that DNA sequences had limited power for accessibility prediction, while both TF binding and HM signals predicted chromatin accessibility with high accuracy. According to the HM model, HM features determined chromatin accessibility in a cell line shared manner, with the prediction power attributing to five core HM types. Results from the TF model indicated that chromatin accessibility was determined by a subset of informative TFs including both cell line-specific and generic TFs. The combined model of both TF and HM signals did not further improve the prediction accuracy, indicating that they provide redundant information in terms of chromatin accessibility prediction. The TFs and HM models can also distinguish the chromatin accessibility of proximal versus distal transcription start sites with high accuracy.
Highlights
Chromatin accessibility is the extent to which nuclear molecules, including Transcription factor (TF), chromatin remodelers and histones, could physically interact with chromatinized DNA [1]
The integrative model for predicting chromatin accessibility Our hypothesis was that the sequence, TF motifs, TF binding, and Histone modification (HM) were associated with chromatin accessibility
The binding signals for most TFs were enriched in the accessible regions while HM signals were enriched in either accessible or non-accessible regions (Fig. 1A-B)
Summary
Chromatin accessibility is the extent to which nuclear molecules, including TFs, chromatin remodelers and histones, could physically interact with chromatinized DNA [1]. Though all associated with chromatin accessibility, there is a lack of quantitative, systematic studies that evaluate the different contributions of each factor during chromatin remodeling. Many methods have been developed to predict the chromatin accessibility using genomic and epigenomic features. Most of them only used DNA sequence information as the feature for prediction, leaving the contribution of other genomic and epigenomic features being un-answered [15,16,17,18]. For the limited studies that integrated DNA sequence with TFs for prediction [14], the different contributions between these factors in chromatin accessibility prediction was not examined. A quantitative chromatin accessibility prediction model that integrates different epigenomic and genomic features is needed
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