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. 2021 Oct 11;13:158. doi: 10.1186/s13073-021-00970-3

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 4 — Activity-by-contact model of enhancer-gene regulation. a ABC model schema. e1 and e2 denote two arbitrary enhancers (solid red circles) for a gene (black arrow). “G” denotes a gene. Both “E” and “e” denote an enhancer. ABC_E,G denotes the ABC score (predicted effect) of a E–G pair. Activity (“A”) estimates the enhancer strength while Contact (“C”) estimates the frequency of the enhancer-gene connection. The ABC score of an enhancer to one gene’s expression is calculated by that enhancer’s effect divided by the total effect of all enhancers for the gene. b ABC model for explaining gene expression differences between OCUM1 and SNU16 cells. Activity is estimated as the level of H3K27ac-enrichment at an enhancer while Contact is quantified as a function of the genomic distance between the enhancer and the TSS of the gene (Contact = Distance⁻¹). c Comparison of ABC score differences and observed gene expression differences between OCUM1 and SNU16 cells. Each dot represents a differentially expressed gene between OCUM1 and SNU16 cells. Activity of an enhancer is estimated as the H3K27ac signal. R: Pearson’s correlation coefficient. P value: Pearson’s correlation test. d GRO-cap data confirms a statistically higher percentage of transcribed enhancers involved in enhancer-promotor interactions compared to H3K27ac-defined enhancers in GM12878 lymphoblastoid cells. Transcribed enhancers are inferred from GRO-cap-based annotations of TSSs. P values were calculated empirically by random shuffling of sequences within H3K27ac-enriched regions. e Comparison of ABC score differences and observed gene expression differences between OCUM1 and SNU16 cells. Activity of an enhancer is estimated as the geometric mean of H3K27ac-enrichment and CapSTARR-seq signal. f Comparison of the HSPB1 expression difference and the ABC score difference between OCUM1 and SNU16 cells in the HSPB1 locus. Predicted E–P connections (dotted red arcs) are based on ABC maps in OCUM1 and SNU16 cells. Observed E–P connections (solid red arcs) are derived from the pcHi-C database