Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor
Open accessAbstract
Chromatin loops juxtapose distal enhancers with active promoters, but their molecular architecture and relationship with transcription remain unclear. In erythroid cells, the locus control region (LCR) and β-globin promoter form a chromatin loop that requires transcription factor GATA1 and the associated molecule Ldb1. We employed artificial zinc fingers (ZF) to tether Ldb1 to the β-globin promoter in GATA1 null erythroblasts, in which the β-globin locus is relaxed and inactive. Remarkably, targeting Ldb1 or only its self-association domain to the β-globin promoter substantially activated β-globin transcription in the absence of GATA1. Promoter-tethered Ldb1 interacted with endogenous Ldb1 complexes at the LCR to form a chromatin loop, causing recruitment and phosphorylation of RNA polymerase II. ZF-Ldb1 proteins were inactive at alleles lacking the LCR, demonstrating that their activities depend on long-range interactions. Our findings establish Ldb1 as a critical effector of GATA1-mediated loop formation and indicate that chromatin looping causally underlies gene regulation.
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LDB1 forms loops independently of both cohesin and CTCF.
“In contrast to YY1 and ZNF143, LDB1 has been shown to form loops independently of both cohesin and CTCF [371, 375].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [371]
The Results section reports that tethering Ldb1’s self-association domain produces an LCR–β-globin promoter loop, and the Discussion identifies Ldb1 self-association as a force behind long-range interactions. Neither passage establishes that these loops form independently of cohesin or CTCF; searches for both terms found no such test or conclusion in our copy. Page numbers were not available. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLDB1 was first identified as a looping factor in the mouse β-globin locus.
“LDB1 was first identified as a looping factor in the mouse β-globin locus [317, 371].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [371]
The Introduction identifies Ldb1 as a factor involved in LCR–β-globin interactions, and the Results show that tethering Ldb1 can produce an LCR–β-globin loop. Our copy does not establish that the mouse β-globin locus was where Ldb1 was first identified as a looping factor; the Introduction cites earlier work on its role there. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe functional significance of the physical approximation of the promoter to the enhancer was demonstrated in experiments on the activation of transcription through the forced formation of enhancer-promoter loops.
“The functional significance of the physical approximation of the promoter to the enhancer was demonstrated in experiments on the activation of transcription through the forced formation of enhancer-promoter loops [87,88].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [88]
Stimulation of promoter activity by forced looping with an enhancer is a strong argument in favor of the loop model.
“Stimulation of promoter activity by forced looping with an enhancer is a strong argument in favor of this model [87,88,110,111].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [88]
Physical contact between enhancer-promoter pairs appears to be sufficient for gene activation.
“and physical contact between enhancer-promoter pairs appears to be sufficient for gene activation.26”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [26]
Tethering the SA domain to the LCR (L-SA) or β-major promoter did not activate βh1-globin expression.
“Tethering the SA domain to the LCR (L-SA in Figure 1) or β-major promoter (Deng et al., 2012, and data not shown) did not activate βh1-globin expression”
From Reactivation of developmentally silenced globin genes by forced chromatin looping (2014) · cites this paper as Deng et al., 2012
In adult type murine erythroid cells, Ldb1 is required for the juxtaposition between the LCR and the adult β-major globin gene.
“In adult type murine erythroid cells, Ldb1 is required for the juxtaposition between the LCR and the adult β-major globin gene (Deng et al., 2012; Song et al., 2007).”
From Reactivation of developmentally silenced globin genes by forced chromatin looping (2014) · cites this paper as Deng et al., 2012
Forced juxtaposition of an enhancer and promoter via chromatin looping can trigger gene activation.
“These results demonstrated that forced juxtaposition of an enhancer and promoter via chromatin looping can trigger gene activation”
From Reactivation of developmentally silenced globin genes by forced chromatin looping (2014) · cites this paper as Deng et al., 2012
Tethered Ldb1 is sufficient for full reconstitution of an LCR-β-globin promoter loop in immature adult erythroid cells in which the globin locus is otherwise unlooped.
“Finally, previous 3C experiments demonstrated the sufficiency of tethered Ldb1 for full reconstitution of an LCR-β-globin promoter loop in immature adult erythroid cells in which the globin locus is otherwise unlooped (Deng et al., 2012).”
From Reactivation of developmentally silenced globin genes by forced chromatin looping (2014) · cites this paper as Deng et al., 2012
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- Authors
- Deng, W., Lee, J., Wang, H., Miller, J., Reik, A., Gregory, P. D., Dean, A., & Blobel, G. A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- National Institutes of Health (US)
- Sangamo BioSciences (United States) (US)
- Corresponding author
- Blobel, Gerd A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 149
- Issue
- 6
- Pages
- 1233-1244
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3372860
- OpenAlex
- W1970831058
- Cited by
- 734
- References
- 49
- Citations by year
- 2026: 22 · 2025: 42 · 2024: 48 · 2023: 54 · 2022: 48 · 2021: 58 · 2020: 60 · 2019: 70 · 2018: 57 · 2017: 50 · 2016: 51 · 2015: 60 · 2014: 62 · 2013: 45 · 2012: 7
- FWCI
- 22.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL119479)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK058044, R01DK054937)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- chromatin looping, locus control region, beta-globin promoter, LDB1, GATA-1, erythroid cells, enhancer-promoter interactions, RNA polymerase II phosphorylation, transcriptional activation
- MeSH terms
- Animals, Cell Line, Cell Separation, Chromatin, DNA-Binding Proteins, Embryo, Mammalian, Erythroblasts, Female, Gene Expression Regulation, Male, Promoter Regions, Genetic, Transcription, Genetic, Zinc Fingers, Protein Structure, Tertiary, GATA1 Transcription Factor, Mice, beta-Globins, LIM Domain Proteins
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