High-Resolution Mapping of Multiway Enhancer-Promoter Interactions Regulating Pathogen Detection
Program in Bioinformatics and Integrative Biology; Program in Molecular Medicine; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Bioinformatics | Genetics and Genomics | Molecular Biology
Eukaryotic gene expression regulation involves thousands of distal regulatory elements. Understanding the quantitative contribution of individual enhancers to gene expression is critical for assessing the role of disease-associated genetic risk variants. Yet, we lack the ability to accurately link genes with their distal regulatory elements. To address this, we used 3D enhancer-promoter (E-P) associations identified using split-pool recognition of interactions by tag extension (SPRITE) to build a predictive model of gene expression. Our model dramatically outperforms models using genomic proximity and can be used to determine the quantitative impact of enhancer loss on gene expression in different genetic backgrounds. We show that genes that form stable E-P hubs have less cell-to-cell variability in gene expression. Finally, we identified transcription factors that regulate stimulation-dependent E-P interactions. Together, our results provide a framework for understanding quantitative contributions of E-P interactions and associated genetic variants to gene expression.
chromosome conformation, cis-regulatory elements, dendritic cells, enhancers, genetic variation, innate immunity, machine learning, multiway promoter interactions, single cell, single molecule
DOI of Published Version
Vangala P, Murphy R, Quinodoz SA, Gellatly K, McDonel P, Guttman M, Garber M. High-Resolution Mapping of Multiway Enhancer-Promoter Interactions Regulating Pathogen Detection. Mol Cell. 2020 Oct 15;80(2):359-373.e8. doi: 10.1016/j.molcel.2020.09.005. Epub 2020 Sep 28. PMID: 32991830; PMCID: PMC7572724. Link to article on publisher's site
Vangala P, Murphy R, Quinodoz SA, Gellatly KJ, McDonel PE, Guttman M, Garber M. (2020). High-Resolution Mapping of Multiway Enhancer-Promoter Interactions Regulating Pathogen Detection. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1016/j.molcel.2020.09.005. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1831