Abstract
BackgroundAssigning chromatin states genome-wide (e.g. promoters, enhancers, etc.) is commonly performed to improve functional interpretation of these states. However, computational methods to assign chromatin state suffer from the following drawbacks: they typically require data from multiple assays, which may not be practically feasible to obtain, and they depend on peak calling algorithms, which require careful parameterization and often exclude the majority of the genome. To address these drawbacks, we propose a novel learning technique built upon the Self-Organizing Map (SOM), Self-Organizing Map with Variable Neighborhoods (SOM-VN), to learn a set of representative shapes from a single, genome-wide, chromatin accessibility dataset to associate with a chromatin state assignment in which a particular RE is prevalent. These shapes can then be used to assign chromatin state using our workflow.ResultsWe validate the performance of the SOM-VN workflow on 14 different samples of varying quality, namely one assay each of A549 and GM12878 cell lines and two each of H1 and HeLa cell lines, primary B-cells, and brain, heart, and stomach tissue. We show that SOM-VN learns shapes that are (1) non-random, (2) associated with known chromatin states, (3) generalizable across sets of chromosomes, and (4) associated with magnitude and multimodality. We compare the accuracy of SOM-VN chromatin states against the Clustering Aggregation Tool (CAGT), an unsupervised method that learns chromatin accessibility signal shapes but does not associate these shapes with REs, and we show that overall precision and recall is increased when learning shapes using SOM-VN as compared to CAGT. We further compare enhancer state assignments from SOM-VN in signals above a set threshold to enhancer state assignments from Predicting Enhancers from ATAC-seq Data (PEAS), a deep learning method that assigns enhancer chromatin states to peaks. We show that the precision-recall area under the curve for the assignment of enhancer states is comparable to PEAS.ConclusionsOur work shows that the SOM-VN workflow can learn relationships between REs and chromatin accessibility signal shape, which is an important step toward the goal of assigning and comparing enhancer state across multiple experiments and phenotypic states.
Highlights
Assigning chromatin states genome-wide is commonly performed to improve functional interpretation of these states
We determined the quality of each sample using the Signal Portion of Tags (SPOT) score defined by Encyclopedia of DNA elements (ENCODE), which approximates signal to noise ratio using the percentage of reads falling into peaks
In general, promoter-associated shape maxima were higher than enhancer-associated shape maxima, which were higher than weak-associated shape maxima; some overlap existed between the groups (Supplementary Table 6 in Additional file 1)
Summary
Assigning chromatin states genome-wide (e.g. promoters, enhancers, etc.) is commonly performed to improve functional interpretation of these states. Computational methods to assign chromatin state suffer from the following drawbacks: they typically require data from multiple assays, which may not be practically feasible to obtain, and they depend on peak calling algorithms, which require careful parameterization and often exclude the majority of the genome. To address these drawbacks, we propose a novel learning technique built upon the Self-Organizing Map (SOM), Self-Organizing Map with Variable Neighborhoods (SOM-VN), to learn a set of representative shapes from a single, genome-wide, chromatin accessibility dataset to associate with a chromatin state assignment in which a particular RE is prevalent. This is typically done using multiple ChIP-seq assays, which require 1–20 million cells per assay [26] or specialized protocols and antibodies [27]
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