Skip to content

Activity-by-Contact (ABC) Model

Summary

The Activity-by-Contact (ABC) model is a prominent predictive framework used to map enhancer-gene regulatory connections. It estimates the relative effect of an enhancer on a gene by multiplying the enhancer's "activity" (chromatin accessibility and active histone modifications) by its "contact" frequency (from 3D chromosome conformation capture techniques like Hi-C). The ABC model serves as a core feature in supervised models such as ENCODE-rE2G.

Overview

Enhancers can regulate target genes across large genomic distances, bypassing neighboring genes to contact specific promoters. The ABC model formalizes a simple quantitative model for this interaction. It assumes that the relative effect of an enhancer $E$ on a promoter $P$ depends on the fraction of total regulatory input to $P$ that comes from $E$:

$$\text{ABC Score for } (E, P) = \frac{\text{Activity}(E) \times \text{Contact}(E, P)}{\sum_{E'} \text{Activity}(E') \times \text{Contact}(E', P)}$$

where: - $\text{Activity}(E)$ is measured using chromatin accessibility (e.g., DNase-seq or ATAC-seq) and/or active enhancer histone marks (such as H3K27ac). - $\text{Contact}(E, P)$ is estimated from Hi-C or other 3D chromatin contact maps. - The denominator sums over all candidate elements $E'$ within a defined window (typically 5 Mb) around the promoter $P$.

Implementations and Refinements

The original ABC model utilized H3K27ac ChIP-seq and DNase-seq for activity, paired with cell-type-specific Hi-C. In the ENCODE Consortium's systematic benchmarking (as of 2026-07-15), the ABC model was updated with: - A reproducible Snakemake pipeline supporting hg38 and multi-replicate peak calling. - DNase-only baseline: Substituting DNase-seq as a standalone proxy for activity when H3K27ac data is unavailable, paired with a tissue-averaged Hi-C Megamap. - Integration into supervised classifiers: The ABC score acts as the single most predictive individual feature within the ENCODE-rE2G and ENCODE-rE2GExtended models.

See Also

  • ENCODE-rE2G — The supervised classifier that builds upon the ABC model.
  • Engreitz Lab — Researchers who pioneered and maintain the ABC model pipeline.

Citations

  • [1] Fulco, C. P. et al. (2019). Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations. Nature Genetics, 51, 1664–1669. DOI: 10.1038/s41588-019-0538-0
  • [2] Gschwind, A. R. et al. (2026). An encyclopedia of human enhancer–gene regulatory interactions. Nature. DOI: 10.1038/s41586-026-10781-4. Source paper: s41586-026-10781-4.pdf