Static and Dynamic DNA Loops form AP-1-Bound Activation Hubs during Macrophage Development
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Abstract
The three-dimensional arrangement of the human genome comprises a complex network of structural and regulatory chromatin loops important for coordinating changes in transcription during human development. To better understand the mechanisms underlying context-specific 3D chromatin structure and transcription during cellular differentiation, we generated comprehensive in situ Hi-C maps of DNA loops in human monocytes and differentiated macrophages. We demonstrate that dynamic looping events are regulatory rather than structural in nature and uncover widespread coordination of dynamic enhancer activity at preformed and acquired DNA loops. Enhancer-bound loop formation and enhancer activation of preformed loops together form multi-loop activation hubs at key macrophage genes. Activation hubs connect 3.4 enhancers per promoter and exhibit a strong enrichment for activator protein 1 (AP-1)-binding events, suggesting that multi-loop activation hubs involving cell-type-specific transcription factors represent an important class of regulatory chromatin structures for the spatiotemporal control of transcription.
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A single enhancer may contact and regulate several promoters, a phenomenon previously seen in macrophages.
“This is consistent with the observation that a single enhancer may contact and regulate several promoters, a phenomenon previously seen in macrophages74.”
From Variant-to-function mapping of late-onset Alzheimer’s disease GWAS signals in human microglial cell models implicates <i>RTFDC1</i> at the <i>CASS4</i> locus (2024) · cites this paper as [74]
The Results section (‘Dynamic re-wiring of chromatin architecture’) describes a macrophage activation hub connecting distal enhancers to the promoters of both TPRG1 and BCL6, with increased expression of both genes. It does not establish that one individual enhancer contacts and regulates both promoters; elsewhere, the paper characterizes hubs chiefly as multiple enhancers connected to a promoter. No page number is available in our copy. (LLM, conf=0.82)
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- Authors
- Phanstiel, D. H., Van Bortle, K., Spacek, D., Hess, G. T., Shamim, M. S., Machol, I., Love, M. I., Aiden, E. L., Bassik, M. C., & Snyder, M. P.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Stanford University (US)
- Baylor College of Medicine (US)
- Corresponding author
- Phanstiel, Douglas H.
- Snyder, Michael P.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 67
- Issue
- 6
- Pages
- 1037-1048.e6
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5610110
- OpenAlex
- W2620165518
- Cited by
- 299
- References
- 24
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 42 · 2023: 34 · 2022: 36 · 2021: 53 · 2020: 29 · 2019: 37 · 2018: 23 · 2017: 3 · 2014: 1
- FWCI
- 10.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- NIH National Human Genome Research Institute (NHGRI) (R00HG008662)
- Damon Runyon Cancer Research Foundation (DRG-2122-12)
- NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (F32DK107112)
- NIH (T32HG000044, HG000044, 1DP2OD008540, U01HL130010, UM1HG009375)
- NIH National Cancer Institute (NCI) (CA142538-07)
- Genentech
- NIH Centers of Excellence in Genomic Science (CEGS) (5P50HG00773502)
- NSF (PHY-1427654)
- NHGRI (HG006193)
- Welch Foundation (Q-1866)
- NVIDIA
- IBM
- a Cancer Prevention Research Institute of Texas (R1304)
- McNair Medical Institute
- President’s Early Career Award
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- DNA loops, 3D genome organization, enhancer activation, AP-1, macrophage differentiation, monocytes, Hi-C, enhancer-promoter interactions, transcriptional regulation
- MeSH terms
- Binding Sites, Cell Differentiation, Chromatin, DNA, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Macrophages, Nucleic Acid Conformation, Phenotype, Protein Binding, Time Factors, Transcription, Genetic, Transcription Factor AP-1, Chromatin Assembly and Disassembly, Cell Line, Tumor, High-Throughput Nucleotide Sequencing
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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