Epigenome overlap measure (EPOM) for comparing tissue/cell types based on chromatin states

Abstract

Background: The dynamics of epigenomic marks in their relevant chromatin states regulate distinct gene expression patterns, biological functions and phenotypic variations in biological processes. The availability of high-throughput epigenomic data generated by next-generation sequencing technologies allows a data-driven approach to evaluate the similarities and differences of diverse tissue and cell types in terms of epigenomic features. While ChromImpute has allowed for the imputation of large-scale epigenomic information to yield more robust data to capture meaningful relationships between biological samples, widely used methods such as hierarchical clustering and correlation analysis cannot adequately utilize epigenomic data to accurately reveal the distinction and grouping of different tissue and cell types.

Methods: We utilize a three-step testing procedure-ANOVA, t test and overlap test to identify tissue/cell-type- associated enhancers and promoters and to calculate a newly defined Epigenomic Overlap Measure (EPOM). EPOM results in a clear correspondence map of biological samples from different tissue and cell types through comparison of epigenomic marks evaluated in their relevant chromatin states.

Results: Correspondence maps by EPOM show strong capability in distinguishing and grouping different tissue and cell types and reveal biologically meaningful similarities between Heart and Muscle, Blood & T-cell and HSC & B-cell, Brain and Neurosphere, etc. The gene ontology enrichment analysis both supports and explains the discoveries made by EPOM and suggests that the associated enhancers and promoters demonstrate distinguishable functions across tissue and cell types. Moreover, the tissue/cell-type-associated enhancers and promoters show enrichment in the disease-related SNPs that are also associated with the corresponding tissue or cell types. This agreement suggests the potential of identifying causal genetic variants relevant to cell-type-specific diseases from our identified associated enhancers and promoters.

Conclusions: The proposed EPOM measure demonstrates superior capability in grouping and finding a clear correspondence map of biological samples from different tissue and cell types. The identified associated enhancers and promoters provide a comprehensive catalog to study distinct biological processes and disease variants in different tissue and cell types. Our results also find that the associated promoters exhibit more cell-type-specific functions than the associated enhancers do, suggesting that the non-associated promoters have more housekeeping functions than the non-associated enhancers.

Fig. 1

Outline of EPOM. The orange box gives the legend of the outline: the rounded rectangles represent data taken as input of EPOM; the diamonds represent methods and analysis used in our work; the rectangles represent results and outcomes of our methods. More details of the testing procedure are given in Fig. 2

Fig. 2

Diagram of EPOM’s three-step testing procedure

Fig. 3

a–d Correspondence maps of EPOM scores saturated at 20 (all the values larger than 20 are set to 20). a Calculated based on associated enhancers (threshold m=14 in t test). b Calculated based on associated promoters (threshold m=14 in t test). c Calculated based on associated enhancers (threshold m=13 in t test). d Calculated based on associated promoters (threshold m=13 in t test). e Correspondence maps of Pearson correlation coefficients calculated from H3K4me1 and H3K27ac signals in candidate enhancers and candidate promoters. Axis colors mark different true tissue/cell types

Fig. 4

a Number of associated enhancers’ potential target genes in each tissue/cell type. b Number of associated promoters’ potential target genes in each tissue/cell type. c–d Proportions are calculated as the number of regions’ potential target genes divided by the number of associated regions. c Proportion of enhancers’ potential target genes in corresponding groups as in (a). d Proportion of promoters’ potential target genes in corresponding groups as in b. Colors of the sub-bars represent the number of tissue/cell types (n) in which the genes are identified, as explained in the legend

Fig. 5

GO enrichment analysis of associated enhancers’ potential target genes. Shown GO terms are at least among the top 10 enriched GO terms in one tissue/cell type. Enrichment scores are calculated as − log10(Bonferroni corrected p−values). Darker colors represent higher scores. The enriched GO terms can be used to infer the biological functions of associated enhancers in each tissue/cell type. To illustrate this, some GO terms are marked in the same colors of the tissue/cell types (see the colorbar on top of the heatmap and the heatmap column labels) in which the terms are enriched

Fig. 6

GO enrichment analysis of associated promoters’ potential target genes. Shown GO terms are at least among the top 10 enriched GO terms in one tissue/cell type. Enrichment scores are calculated as − log10(Bonferroni corrected p−values). Darker colors represent higher scores. The enriched GO terms can be used to infer the biological functions of associated promoters in each tissue/cell type. To illustrate this, some GO terms are marked in the same colors of the tissue/cell types (see the colorbar on top of the heatmap and the heatmap column labels) in which the terms are enriched

Fig. 7

Characteristic GO terms enriched in different tissue/cell types. These terms are the characteristic ones extracted from Figs. 5 and 6. The second (fourth) column lists the GO terms only enriched in associated enhancers (promoters); the third column lists the GO terms enriched in both associated enhancers and promoters

Fig. 8

DO enrichment analysis in associated enhancers in each tissue/cell type. Shown DO terms are at least significantly enriched in one tissue/cell type. Enrichment scores are calculated as − log10(Bonferroni corrected p−values). Darker colors represent higher scores. For each tissue/cell type, its enriched DO term is marked in the same color as the tissue/cell label if there is a straightforward relationship between the DO term and the tissue/cell type