Systematic classification of non-coding RNAs by epigenomic similarity

Abstract

Background: Even though only 1.5% of the human genome is translated into proteins, recent reports indicate that most of it is transcribed into non-coding RNAs (ncRNAs), which are becoming the subject of increased scientific interest. We hypothesized that examining how different classes of ncRNAs co-localized with annotated epigenomic elements could help understand the functions, regulatory mechanisms, and relationships among ncRNA families.

Results: We examined 15 different ncRNA classes for statistically significant genomic co-localizations with cell type-specific chromatin segmentation states, transcription factor binding sites (TFBSs), and histone modification marks using GenomeRunner (http://www.genomerunner.org). P-values were obtained using a Chi-square test and corrected for multiple testing using the Benjamini-Hochberg procedure. We clustered and visualized the ncRNA classes by the strength of their statistical enrichments and depletions.

Conclusions: Searching for statistically significant associations between ncRNA classes and epigenomic elements permits detection of potential functional and/or regulatory relationships among ncRNA classes, and suggests cell type-specific biological roles of ncRNAs.

Figure 1

The hierarchy of ncRNA classes. Adapted from [45].

Figure 2

Variability of enriched associations per ncRNA class. A) The standard deviation of ncRNA classes enrichment p-values, adjusted for multiple testing, tested for associations with all epigenomic elements. B) Positive correlation between the size of an ncRNA class and the variability of their associations with all epigenomic elements.

Figure 3

Correlations among the ncRNA classes based on their enriched or depleted associations with all epigenomic elements. If two classes exhibit similar enrichment/depletion patterns, they would be positively correlated (yellow gradient). Patterns of the opposite associations will be negatively correlated (blue gradient).

Figure 4

Boxplots of -log₁₀(p-value) distributions for different classes of ncRNAs. Red/blue horizontal lines represent p-value = 0.01 threshold for over- and underrepresentation, respectively. P-values were multiple testing corrected using Benjamini-Hochberg procedure. A) Histone modification marks associations; B) Chromatin states associations; C) Transcription factor binding sites associations.

Figure 5

Heatmaps of -log₁₀(p-value) enriched associations. Blue-yellow gradient highlights the significance of under-/overrepresented associations of ncRNA classes (X axis) with corresponding epigenomic elements (Y axis). Panels A), C), and E) represent associations of piRNA and tRNA classes with the Histone modification marks, chromatin state segmentation, and transcription factor binding sites, respectively. Only associations with p.adj<10^-20 are shown for clarity. Panels B), D), and F) show the same associations for other ncRNA classes