Integrative Chromatin Accessibility and RNA Framework for Gene Regulatory Networks.

CraftGRN

Introduction

CraftGRN is a modular framework for integrating chromatin accessibility profiles from ATAC-seq with matched RNA-seq expression data to infer condition-specific transcription factor binding sites and reconstruct dynamic gene regulatory networks.

CraftGRN helps users:

• Collapse overlapping TF motif footprints into consensus, site- and motif-nonredundant footprint clusters.
• Infer condition-specific canonical and non-canonical TF binding sites by correlating TF expression with footprint or chromatin accessibility scores.
• Refine TF->TFBS->gene regulatory priors using enhancer-gene maps, genomic proximity, or user-supplied chromatin interaction data.
• Extract active regulatory links within each condition and compare links between conditions.
• Learn regulatory topics from RNA and footprint signals using topic modeling and VAE-based representations.
• Generate summaries and visualizations for topic- and condition-specific regulatory programs.

Installation

CraftGRN can be installed from GitHub:

# Using remotes
remotes::install_github("oncologylab/craftgrn")

# or using pak
pak::pak("oncologylab/craftgrn")

Common CRAN and Bioconductor dependencies can be installed with:

install.packages(c("igraph", "ggplot2", "data.table", "BiocManager"))
BiocManager::install(c("DESeq2", "GenomicRanges", "SummarizedExperiment"))

Demo Data

CraftGRN keeps demo datasets outside the source package so installation remains small and CRAN-friendly. The package helper reports any configured external demo bundles:

craftgrn::craftgrn_demo_data_info()

No external demo bundle is currently configured. To run your own project, point CraftGRN at a project-level YAML file:

config <- "project.yaml"
module1_dir <- file.path(tempdir(), "predict_tf_binding_sites")

omics <- craftgrn::load_prep_multiomic_data(
  config = config,
  label_col = "strict_match_rna",
  do_preprocess = FALSE,
  verbose = TRUE
)

module1 <- craftgrn::predict_tfbs(
  omics_data = omics,
  out_dir = module1_dir,
  output_format = "auto",
  write_outputs = TRUE,
  write_stats = FALSE,
  verbose = TRUE
)

Troubleshooting:

• If craftgrn_demo_data_info() returns zero rows, no public demo bundle is currently advertised by this package version.
• If paths fail after moving a project folder, keep project.yaml in the project directory and pass that config path explicitly. A portable project config should use base_dir: ".".
• If memory is limited, start with load_prep_multiomic_data() and Module 1 before running Module 2.

Pipeline Overview

CraftGRN is organized as a three-module workflow.

Module 1: Predict TF Binding Sites

Module 1 loads matched ATAC, RNA, metadata, and optional footprint score files, then prepares a multiomic data object for downstream regulatory analysis.

Primary package functions:

• load_prep_multiomic_data() loads, filters, aligns, and prepares multiomic inputs from a YAML configuration file. When outputs are enabled, it also writes 01_fp_scores_qn_<db>.csv, the quantile-normalized footprint score matrix used downstream.
• predict_tfbs() performs direct-bound footprint filtering and TF binding site prediction across matched conditions.
• build_module1_qc_report() writes an HTML QC report for run parameters, input gates, canonical support, correlation diagnostics, predicted TFBS chunk integrity, top TFs/FPs, condition support, warning checks, and related Module 1 artifacts. The report uses multiple static plot types, including processing funnels, density curves, scatter summaries, heatmaps, lollipop rank plots, and cumulative curves.

Module 2: Connect TFs to Target Genes

Module 2 links TF binding sites to candidate target genes using enhancer-gene maps, genomic distance windows, or 3D chromatin interaction priors. Candidate TF->TFBS->target links are filtered by condition-specific expression, binding, footprint or peak signal, and cross-condition correlation evidence.

Primary package functions:

• predict_tf_targets() predicts TF target genes from predicted TFBS, TF-target correlations, FP-target correlations, genomic proximity, and optional regulatory priors.
• build_module2_qc_report() writes an HTML QC report for compact handoff checks, TF-target and FP-target filters, candidate source and distance-to-TSS evidence, final-link integrity, condition activity, warning checks, top TF/target/FP summaries, and related browser reports. The report combines relational flow diagrams, density and cumulative distance plots, scatter summaries, heatmaps, and lollipop rank plots.

Module 3: Learn Regulatory Topics and Visualize Differential GRNs

Module 3 compares condition-specific regulatory links, builds joint RNA and footprint document-term matrices, trains topic models, assigns regulatory links to topics, and summarizes pathway and master TF programs.

Primary package functions:

• run_topic_modeling() runs one selected Module 3 topic-document method with a flat standard output layout, compact topic-link outputs, and a QC report. The selected method, K value or K grid, WarpLDA iterations, and topic-link output mode can be stored in the project YAML config.
• module3_prepare_differential_links() prepares filtered differential links from Module 2 predicted links and condition comparisons.
• module3_construct_docs() builds reusable topic-document, document-term, and sparse matrix caches for step-by-step inspection.
• module3_train_topic_models() trains regulatory topic models across a user-defined topic-number grid using the native warp_omp WarpLDA sampler by default. Use warplda_sampler = "warp_ref" only when you need a slower sequential fixed-seed reference run from the native backend.
• module3_extract_topics() assigns links and terms to selected regulatory topics.
• build_module3_qc_report() summarizes topic inputs, model outputs, differential links, and top differential TFs.
• visualize_topic_modeling_results() exports topic-modeling review browsers, and visualize_differential_grns() exports an interactive differential GRN network browser with comparison, direction, Top TF, and Top link controls.

For regular package runs, keep one selected Module 3 setup in project.yaml, for example:

topic_method: comparison_aggr_multivi
topic_k: 10
warplda_iterations: 2000
topic_link_output: pass
pathway_backend: enrichly

topic_benchmark_enabled: false
topic_benchmark_methods: []
topic_benchmark_k_grid: []

pathway_backend: enrichly uses local cached pathway libraries when the optional enrichly package is installed; pathway_backend: enrichr keeps the web API backend. Benchmark grids are optional and should be enabled only for method-comparison experiments.

Get Started

For a module-by-module tutorial, see the Get started article.

Documentation

• Website: https://oncologylab.github.io/craftgrn/
• Reference: https://oncologylab.github.io/craftgrn/reference/
• Issues: https://github.com/oncologylab/craftgrn/issues

Citation

Li, Y., Yi, C. et al. (in preparation). CraftGRN: Integrative ATAC-RNA framework for condition-specific gene regulatory network analysis.

License

This project is licensed under the GNU General Public License v3.0.