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High-Resolution Mapping of Multiway Enhancer-Promoter Interactions Regulating Pathogen Detection

Vangala, Pranitha and Murphy, Rachel and Quinodoz, Sofia A. and Gellatly, Kyle and McDonel, Patrick and Guttman, Mitchell and Garber, Manuel (2020) High-Resolution Mapping of Multiway Enhancer-Promoter Interactions Regulating Pathogen Detection. Molecular Cell, 80 (2). pp. 359-373. ISSN 1097-2765. PMCID PMC7572724. https://resolver.caltech.edu/CaltechAUTHORS:20201012-163632672

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.molcel.2020.09.005DOIArticle
ORCID:
AuthorORCID
Murphy, Rachel0000-0003-1106-1450
Quinodoz, Sofia A.0000-0003-1862-5204
Guttman, Mitchell0000-0003-4748-9352
Garber, Manuel0000-0001-8732-1293
Additional Information:© 2020 Elsevier. Received 22 February 2020, Revised 4 June 2020, Accepted 4 September 2020, Available online 28 September 2020. We thank Athma Pai, Oliver Rando, John Harris, Kate Fitzgerald, and members of the Garber Lab for valuable discussions and comments. We thank Meenakshi Kagda and Jennifer Jou for help managing data submission to ENCODE. We also thank Inna-Marie Strazhnik for help with graphical abstract. This project was supported by NHGRI grants U01 HG007910 and R21CA236594 (M. Garber), NIH 4DN grants U01 DA040612 and U01 HL130007, and the NYSCF (M. Guttman). M. Guttman is a NYSCF-Robertson Investigator. Author Contributions. Conceptualization, Formal Analysis, and Data Curation, P.V. and M. Garber; Methodology, P.V., R.M., S.A.Q., K.G., P.M., M. Guttman, and M. Garber; Resources, M. Garber, and M. Guttman; Writing, P.V., M. Guttman, and M. Garber; Supervision and Funding Acquisition, M. Garber. Declaration of Interests. S.A.Q. and M. Guttman are inventors on a provisional patent on the SPRITE method.
Funders:
Funding AgencyGrant Number
NIHU01 HG007910
NIHR21CA236594
NIHU01 DA040612
NIHU01 HL130007
New York Stem Cell FoundationUNSPECIFIED
Subject Keywords:innate immunity; dendritic cells; enhancers; genetic variation; cis-regulatory elements; machine learning; chromosome conformation; single molecule; single cell; multiway promoter interactions
Issue or Number:2
PubMed Central ID:PMC7572724
Record Number:CaltechAUTHORS:20201012-163632672
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201012-163632672
Official Citation:Pranitha Vangala, Rachel Murphy, Sofia A. Quinodoz, Kyle Gellatly, Patrick McDonel, Mitchell Guttman, Manuel Garber, High-Resolution Mapping of Multiway Enhancer-Promoter Interactions Regulating Pathogen Detection, Molecular Cell, Volume 80, Issue 2, 2020, Pages 359-373.e8, ISSN 1097-2765, https://doi.org/10.1016/j.molcel.2020.09.005. (http://www.sciencedirect.com/science/article/pii/S1097276520306134)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:106010
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:13 Oct 2020 17:26
Last Modified:20 Oct 2020 19:10

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