The DOI matches its Crossref record; 54 of the 55 references it cites were found in a registry or an index; none of the 33 sources its claims cite is checked for support yet.
Reactivation of Developmentally Silenced Globin Genes by Forced Chromatin Looping
Open accessAbstract
Distal enhancers commonly contact target promoters via chromatin looping. In erythroid cells, the locus control region (LCR) contacts β-type globin genes in a developmental stage-specific manner to stimulate transcription. Previously, we induced LCR-promoter looping by tethering the self-association domain (SA) of Ldb1 to the β-globin promoter via artificial zinc fingers. Here, we show that targeting the SA to a developmentally silenced embryonic globin gene in adult murine erythroblasts triggers its transcriptional reactivation. This activity depends on the LCR, consistent with an LCR-promoter looping mechanism. Strikingly, targeting the SA to the fetal γ-globin promoter in primary adult human erythroblasts increases γ-globin promoter-LCR contacts, stimulating transcription to approximately 85% of total β-globin synthesis, with a reciprocal reduction in adult β-globin expression. Our findings demonstrate that forced chromatin looping can override a stringent developmental gene expression program and suggest a novel approach to control the balance of globin gene transcription for therapeutic applications.
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TL;DR
Forced chromatin looping by tethering the Ldb1 self-association domain to developmentally silenced globin promoters reactivated embryonic/fetal globin expression in adult erythroid cells. In human adult erythroblasts, targeting the γ-globin promoters raised γ-globin to ~85% of total β-globin synthesis and reduced adult β-globin expression.
Key findings
- Tethering Ldb1 SA to the murine embryonic βh1-globin promoter activated βh1-globin transcription: 368-fold in G1E cells, 26-fold in GATA1-replete cells (~15% of total β-globin), and almost 800-fold in primary adult murine erythroblasts (>30% of total β-globin synthesis).
- βh1-SA activation required the LCR: induction was completely abrogated in erythroid cells from ΔLCR mice, while basal βh1 transcription was unaffected.
- In primary adult human erythroblasts, GG1-SA targeting γ-globin promoters increased γ-globin to ~85% of total globin synthesis versus ~25% in controls, with a ~2.5-fold increase normalized to α-globin and reduced β-globin transcription (13.5% vs. control; 18.1% vs. GG1-Only).
- 3C showed GG1-SA increased LCR–γ-globin contacts and decreased LCR–adult β-globin contacts, supporting a competitive looping mechanism; HPLC also showed increased HbF and reduced HbA/HbA2.
Methods
- Artificial zinc finger proteins were fused to the Ldb1 SA domain and introduced by retroviral or lentiviral infection into G1E murine erythroblasts, primary murine E13.5 fetal liver erythroblasts (wild-type or ΔLCR/ΔLCR), K562 cells, and primary human CD34+ cells from bone marrow or peripheral blood differentiated toward erythroid lineage.
- Binding and expression were assessed by ChIP, RT-qPCR, flow cytometry/immunostaining, HPLC for hemoglobins, and chromosome conformation capture (3C).
- Key genetic test used erythroid cells from mice lacking the LCR to determine whether βh1-SA activity depended on long-range LCR action.
Limitations
- The paper states that 3C for βh1-globin in G1E cells was not reliable because of high basal signals and insufficient signal-to-noise, so LCR dependence was tested genetically with ΔLCR mice instead.
- The paper notes donor variation in basal γ-globin expression (<10% to 50% of total globin synthesis) and sizeable error bars in 3C, requiring normalization and individual-sample plotting.
- The paper states that βh1-SA impaired expression of a few erythroid genes (Band3, AHSP, Alas2) in murine cells, likely via dominant-negative effects at high expression; human SA-fusion proteins did not inhibit orthologous genes. Evident from the text: the therapeutic strategy was tested in cultured primary cells, not in patients or in vivo disease models, and the paper notes that strengths and weaknesses must be considered before human use.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, total hemoglobin production remained unchanged between controls and GG1-SA containing cells (Figure 5B)”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > GG1-SA mediated induction of fetal hemoglobin in peripheral blood derived erythroid precursor cells
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In the paper
“While the loss of the LCR had no impact on basal level βh1-globin transcription”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > βh1-SA activation of βh1-globin expression is LCR-dependent
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In the paper
“GG1-SA expression led to a dramatic increase in the percentage of HbF compared to uninfected controls or GG1-Only (Figure 5A, S5A, and data not shown).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > GG1-SA mediated induction of fetal hemoglobin in peripheral blood derived erythroid precursor cells
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In the paper
“We found that zinc finger mediated tethering of the SA domain of Ldb1 to the murine embryonic βh1-globin promoter activated transcription in an adult type erythroblast cell line and primary definitive erythroid cells.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
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In the paper
“Remarkably, GG1-SA expressing cells produced γ-globin approximating 85% of total globin synthesis (defined as γ-globin plus β-globin) compared with ~25% in GFP negative cells (Figure 4D).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > Zinc finger-SA mediated activation of γ-globin transcription in primary adult human erythroid cells
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In the paper
“βh1-SA activated βh1-globin transcription by almost 800-fold compared to empty vector control (Figure 2B)”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > βh1-SA-mediated activation of embryonic globin gene expression in primary adult erythroblasts
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In the paper
“βh1-globin mRNA levels were increased 368-fold over non-expressing G1E cells or cells that express a zinc finger protein targeting HS2 of the LCR (L-SA) (Figure 1C).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > βh1-SA mediated activation of an embryonic globin gene in adult erythroblasts
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Second, increases in embryonic or fetal globin gene expression were accompanied by a reciprocal decrease in adult β-globin expression, consistent with competition for long-range LCR activity.”
- Also stated in: § Discussion · plain
“First, increases in fetal γ-globin expression were accompanied by reduced adult β-globin expression.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Discussion · plain
In the paper
“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”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > βh1-SA mediated activation of an embryonic globin gene in adult erythroblasts
What the sources say
- Not checked yetcites Deng et al., 2012 source
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In the paper
“The reciprocal alteration in fetal versus adult globin gene transcription was reflected in corresponding changes in contact frequencies with the LCR.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
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- It may state two separate claims as one. 16
- Probably not a substantial claim. 9
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GG1-SA resulted in nearly pancellular HbF expression whereas GG1-Only triggered expression merely in a subset of cells (Figure 6)”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > Cellular distribution of γ-globin protein in adult erythroid cells containing GG1-SA
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In the paper
“Third, 3C experiments revealed that GG1-SA expression strongly stimulated γ-globin promoter-LCR interactions with a concomitant decrease in β-globin-LCR contacts.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, βh1-SA induced βh1-globin levels 26-fold over control cells, amounting to ~15% of total β-globin expression compared to ~0.5% in vector only containing cells (Figure 1C,D).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > βh1-SA mediated activation of an embryonic globin gene in adult erythroblasts
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Primary human erythroid cells expressing the SA domain fused to a zinc finger moiety that targets the γ-globin promoters produced high quantities of γ-globin mRNA and protein in the vast majority of cells with an accompanying reduction in adult type globin expression.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
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In the paper
“We observed that βh1-SA not only activated βh1-globin expression but also to some degree the expression of εy-globin, which resides closer to the LCR than βh1-globin.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
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In the paper
“However, even under the most restrictive conditions as are found in murine cells, the silent βh1-gene promoter remains accessible to βh1-SA and allows for activation of βh1-globin expression up to ~30 % of total β-globin synthesis.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Specifically, in immature murine erythroblasts in which the β-globin promoter is not in contact with the LCR, tethering of Ldb1 to the promoter via artificial zinc finger (ZF) proteins established an LCR-promoter loop similar to that observed in mature erythroid cells and stimulated transcription (Deng et al., 2012).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
What the sources say
- Not checked yetcites Deng et al., 2012
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The self-association (SA) domain of Ldb1 was sufficient for this activity.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
What the sources say
- Not checked yetcites Deng et al., 2012
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In the paper
“Together these results demonstrate that GG1-SA strongly induces the expression of γ-globin with resulting loss in β-globin transcription.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > Zinc finger-SA mediated activation of γ-globin transcription in primary adult human erythroid cells
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these results demonstrate potent induction of HbF by GG1-SA at distinct stages of erythroid differentiation and independent of stem cell source.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > GG1-SA mediated induction of fetal hemoglobin in peripheral blood derived erythroid precursor cells
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In the paper
“Prior studies involving transgenic mice suggested that genomic proximity to the LCR correlates with the ability to compete for LCR activity, presumably because closer genes have a higher probability of forging a productive interaction (Bauchwitz and Costantini, 2000; Hanscombe et al., 1991; Peterson and Stamatoyannopoulos, 1993; Tanimoto et al., 1999).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
What the sources say
- Not checked yetcites Bauchwitz and Costantini, 2000
- Not checked yetcites Hanscombe et al., 1991
- Not checked yetcites Peterson and Stamatoyannopoulos, 1993
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“In primitive murine erythroid cells the LCR loops to the embryonic type β-globin gene promoters (εy and βh1), whereas in definitive erythroid cells the LCR exclusively contacts the adult type β-globin genes (β-major and β-minor) with the intervening embryonic globin genes looped out (Palstra et al., 2003).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
What the sources say
- Not checked yetcites Palstra et al., 2003
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In sum, tethering the SA portion of Ldb1 to the fetal globin promoters promotes their juxtaposition with the LCR leading to transcription activation with accompanying reduction in the expression of adult globin genes.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > GG1-SA induces γ-globin promoter-LCR looping
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In the paper
“Several transcription factors have been implicated in loop formation at the β-globin locus, including Klf1, GATA1, and its co-regulators Ldb1 and FOG1 (Drissen, 2004; Song et al., 2007; Vakoc et al., 2005).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
What the sources say
- Not checked yetcites Drissen, 2004
- Not checked yetcites Song et al., 2007
- Not checked yetcites Vakoc et al., 2005
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that it does not substitute for the LCR by simply enhancing promoter activity, but instead requires long-range LCR action.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
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In the paper
“Five ZFs were FLAG tagged and screened by anti-FLAG ChIP for in vivo binding to the βh1 promoter in G1E cells.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > EXPERIMENTAL PROCEDURES > Artificial Zinc Finger Design
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In the paper
“The 3C signals were normalized to template standards generated from a locus-specific BAC and to 3C signals from the tubulin locus.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > EXPERIMENTAL PROCEDURES > Chromosome Conformation Capture (3C)
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In the paper
“Cell purity was confirmed by post sort flow cytometry.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > EXPERIMENTAL PROCEDURES > Two Phase Differentiation of Bone Marrow Derived Human CD34+ Cells
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In the paper
“Indeed, Bcl11a, a potent silencing factor of the γ-globin genes in human cells, does not detectably bind to the γ-globin gene promoters but appears to regulate the looped configuration of the locus (Xu et al., 2010).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
What the sources say
- Not checked yetcites Xu et al., 2010
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“To eliminate variability between donor samples, interaction frequencies between the anchor fragment and the fragment encompassing the Gγ-globin gene (Figure 7A) or the β-globin (Figure S6B) from the GG1-SA sample of each donor were set to one.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > EXPERIMENTAL PROCEDURES > Chromosome Conformation Capture (3C)
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In the paper
“Chosen target sequences were within the DNase I hypersensitive region to facilitate access but avoid interference with known transcription factor binding sites.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > EXPERIMENTAL PROCEDURES > Artificial Zinc Finger Design
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None of the sources cited for this claim have been checked yet.
In the paper
“This agrees with the notion that the LCR is incapable of interacting with multiple globin promoters at once but instead contacts either the fetal or adult genes (Enver et al., 1990; Wijgerde et al., 1995).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
What the sources say
- Not checked yetcites Enver et al., 1990
- Not checked yetcites Wijgerde et al., 1995
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In the paper
“ZFs were assembled from two-finger units and screened for DNA binding by ELISA assay in vitro as described (Bartsevich et al., 2003).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > EXPERIMENTAL PROCEDURES > Artificial Zinc Finger Design
What the sources say
- Not checked yetcites Bartsevich et al., 2003
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The paper relies on this without support.
As erythroid cells undergo maturation, the ratio of fetal to adult hemoglobin declines.
“As erythroid cells undergo maturation, the ratio of fetal to adult hemoglobin declines.”
The paper relies on this without support.
In normal adults, total fetal hemoglobin synthesis ranges below 3% but is concentrated in a small fraction of cells with high fetal hemoglobin expression (F-cells).
“Second, in normal adults, total fetal hemoglobin synthesis ranges below 3% but is concentrated in a small fraction of cells with high fetal hemoglobin expression (F-cells).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Ectopic tethering of LDB1 to chromatin is sufficient for loop formation, increased deposition of the enhancer mark H3K4me1 and transcriptional activation [372, 374].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [374]
Experimental — accuracy not yet measuredIn the citing paper
“Our observations support a model where dynamic chromatin looping from enhancer regions triggers gene activation (Deng et al., 2014), although clear violations of this principle exist, as previously seen in Drosophila, where many E-P loops are pre-established (Ghavi-Helm et al., 2014).”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Deng et al., 2014
Citations
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Metadata
- Authors
- Deng, W., Rupon, J. W., Krivega, I., Breda, L., Motta, I., Jahn, K. S., Reik, A., Gregory, P. D., Rivella, S., Dean, A., & Blobel, G. A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- National Institutes of Health (US)
- Weill Cornell Medicine (US)
- Sangamo BioSciences (United States) (US)
- Corresponding author
- Blobel, Gerd A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 158
- Issue
- 4
- Pages
- 849-860
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4134511
- OpenAlex
- W2121659981
- Cited by
- 443
- References
- 55
- Citations by year
- 2026: 15 · 2025: 28 · 2024: 21 · 2023: 29 · 2022: 25 · 2021: 43 · 2020: 36 · 2019: 43 · 2018: 60 · 2017: 55 · 2016: 45 · 2015: 38 · 2014: 4
- FWCI
- 19.42
- 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 (1RO1HL119479, 5R37DK058044)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK015508)
- American Heart Association (13POST16950014)
- Associazione Italiana per la Lotta al Neuroblastoma (FP7-HEALTH-2012-INNOVATION, NHLBI-5R01HL102449)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- chromatin looping, locus control region, beta-globin gene, embryonic globin, transcriptional reactivation, erythroid cells, gene silencing, globin gene regulation, erythroblasts
- MeSH terms
- Animals, Chromatin, Embryo, Mammalian, Erythroblasts, Fetal Hemoglobin, Genetic Techniques, Hemoglobinopathies, Humans, Transcriptional Activation, Antigens, CD34, Locus Control Region, Mice, beta-Globins, Primary Cell Culture
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