Modeling cis-regulation with a compendium of genome-wide histone H3K27ac profiles

Genome Res. 2016 Oct;26(10):1417-1429. doi: 10.1101/gr.201574.115. Epub 2016 Jul 27.


Model-based analysis of regulation of gene expression (MARGE) is a framework for interpreting the relationship between the H3K27ac chromatin environment and differentially expressed gene sets. The framework has three main functions: MARGE-potential, MARGE-express, and MARGE-cistrome. MARGE-potential defines a regulatory potential (RP) for each gene as the sum of H3K27ac ChIP-seq signals weighted by a function of genomic distance from the transcription start site. The MARGE framework includes a compendium of RPs derived from 365 human and 267 mouse H3K27ac ChIP-seq data sets. Relative RPs, scaled using this compendium, are superior to superenhancers in predicting BET (bromodomain and extraterminal domain) -inhibitor repressed genes. MARGE-express, which uses logistic regression to retrieve relevant H3K27ac profiles from the compendium to accurately model a query set of differentially expressed genes, was tested on 671 diverse gene sets from MSigDB. MARGE-cistrome adopts a novel semisupervised learning approach to identify cis-regulatory elements regulating a gene set. MARGE-cistrome exploits information from H3K27ac signal at DNase I hypersensitive sites identified from published human and mouse DNase-seq data. We tested the framework on newly generated RNA-seq and H3K27ac ChIP-seq profiles upon siRNA silencing of multiple transcriptional and epigenetic regulators in a prostate cancer cell line, LNCaP-abl. MARGE-cistrome can predict the binding sites of silenced transcription factors without matched H3K27ac ChIP-seq data. Even when the matching H3K27ac ChIP-seq profiles are available, MARGE leverages public H3K27ac profiles to enhance these data. This study demonstrates the advantage of integrating a large compendium of historical epigenetic data for genomic studies of transcriptional regulation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Animals
  • Cell Line, Tumor
  • Epigenesis, Genetic
  • Genome, Human
  • Histone Code*
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Mice
  • Models, Genetic*


  • Histones