Andrews, G. R. | Search bioRxiv

bioRxiv2026

Architectural chromatin interactions provide a framework for context-dependent gene regulation

Gene regulation depends on coordinated interactions between promoters and distal cis-regulatory elements, yet understanding how these regulatory elements communicate remains a fundamental challenge in mammalian genomics. Chromatin interaction assays provide one approach for identifying potential regulatory relationships, but interpreting the biological significance of individual interactions remains difficult; chromatin interactions comprise multiple biologically distinct classes that are only partially captured by any single assay. Here, we integrate Hi-C, RNAPII ChIA-PET, and CTCF ChIA-PET with the ENCODE Registry of candidate cis-regulatory elements (cCREs) and complementary functional genomic datasets to develop an integrative framework for classifying and interpreting promoter-centric chromatin interactions. Using this framework, we identify a distinct class of candidate architectural promoter-enhancer interactions that are characterized by increased recurrence across cellular contexts, broader promoter connectivity, and reduced dependence on linear genomic proximity. We further show that many regulatory elements anchoring these interactions transition between enhancer and CTCF-only states while maintaining stable chromatin interactions. These dual-state regulatory elements also acquire context-specific transcription factor inputs within evolutionarily conserved architectural scaffolds, suggesting that stable chromatin architecture can be repeatedly repurposed for new regulatory functions. Genes connected to these dual-state regulatory elements are enriched for developmental and signaling pathways and exhibit increased expression specificity across cell types, consistent with specialized roles in context-dependent gene regulation. Together, our findings provide a biologically informed framework for classifying and interpreting chromatin interactions and support a model in which conserved chromatin architecture provides a stable foundation upon which new regulatory programs evolve.

genomics↗

bioRxiv2021

Factorbook: an Updated Catalog of Transcription Factor Motifs and Candidate Regulatory Motif Sites

The human genome contains roughly 1,600 transcription factors (TFs) (1), DNA-binding proteins recognizing characteristic sequence motifs to exert regulatory effects on gene expression. The binding specificities of these factors have been profiled both in vitro, using techniques such as HT-SELEX (2), and in vivo, using techniques including ChIP-seq (3, 4). We previously developed Factorbook, a TF-centric database of annotations, motifs, and integrative analyses based on ChIP-seq data from Phase II of the ENCODE Project. Here we present an update to Factorbook which significantly expands the breadth of cell type and TF coverage. The update includes an expanded motif catalog derived from thousands of ENCODE Phase II and III ChIP-seq experiments and HT-SELEX experiments; this motif catalog is integrated with the ENCODE registry of candidate cis-regulatory elements to annotate a comprehensive collection of genome-wide candidate TF binding sites. The database also offers novel tools for applying the motif models within machine learning frameworks and using these models for integrative analysis, including annotation of variants and disease and trait heritability. We will continue to expand the resource as ENCODE Phase IV data are released.

bioinformatics↗