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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.
Overview
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Written from the paper’s full text.
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
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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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In the paper
“Correspondingly, adult hemoglobin levels (HbA and HbA2) declined markedly.”
§ 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“First, deletion of the LCR essentially abrogated the effects of the tethered Ldb1 SA domain, 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
“In adult erythroid cells, re-directing the LCR to the silenced embryonic or fetal β-type globin promoters by targeted tethering of the Ldb1 SA domain strongly activated transcription at the expense of the adult β-globin genes, thus at least partially reversing the developmental gene switch (Figure 7B).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
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In the paper
“GG1-SA targeting was highly specific for the γ-globin promoters with little or no signal at the other globin promoters (Figure 4B).”
§ 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
“GG1-SA expression established a strong interaction between the LCR and the γ-globin genes that is absent in control cells (Figure 7).”
§ 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
“GG1-SA induced a ~2.5-fold increase in γ-globin expression compared to GG1-Only and control (sorted GFP negative cells) populations (Figure 4E, S4D).”
§ 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: passes- Rests on an assumption: As erythroid cells undergo maturation, the ratio of fetal to adult hemoglobin declines.
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
“it completely abrogated the induction of βh1-globin expression seen in the wild type mice (Figure 3B).”
§ 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
“Importantly, GG1-SA expression resulted in a marked reduction in β-globin transcription (13.5% vs. control and 18.1% vs. GG1-Only) (Figure 4E and S4D).”
§ 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: passes- Rests on an assumption: As erythroid cells undergo maturation, the ratio of fetal to adult hemoglobin declines.
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
“exceeding 30% of total β-globin synthesis (Figure 2C).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > βh1-SA-mediated activation of embryonic globin gene expression in primary adult erythroblasts
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“This activity was abrogated in erythroid cells from mice in which the LCR had been deleted”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
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In the paper
“Importantly, β-major expression was slightly reduced in both βh1-SA expressing populations (Figure 2B,S2A)”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > βh1-SA-mediated activation of embryonic globin gene expression in primary adult erythroblasts
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“Additionally, interactions between the LCR and the adult globin genes (δ- and β-globin) were diminished”
§ 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
“Chromatin immunoprecipitation (ChIP) revealed specific binding of βh1-SA to the βh1-globin promoter but not the promoters of the other β-like globin genes (Figure 1B).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > βh1-SA mediated activation of an embryonic globin gene in adult erythroblasts
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In the paper
“Finally, marked effects in fetal globin reactivation were achieved with relatively low levels of GG1-SA transgene expression (<1% of globin genes)”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
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In the paper
“However, GG1-SA expression raised fetal globin expression in the vast majority of transduced cells.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
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
“Similar to βh1-globin, εy-globin up-regulation was dependent on the LCR.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
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In the paper
“Tethering the SA domain did not activate murine embryonic genes to the same level as the human fetal genes.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
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In the paper
“In erythroid cells, a powerful distal enhancer called the locus control region (LCR), composed of multiple DNase I hypersensitive sites (HSs), is in physical proximity to the β-globin genes in a developmentally dynamic manner (Carter et al., 2002; Tolhuis et al., 2002).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
What the sources say
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In the paper
“More broadly, they exemplify controlled manipulation of chromatin folding in the nucleus as a novel and powerful strategy to modulate, positively or negatively, the transcription of designated genes.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
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In the paper
“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).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
What the sources say
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In the paper
“Central to the mechanism of globin gene switching is the exclusive interaction between the LCR and globin gene promoters at distinct developmental stages (Carter et al., 2002; Palstra et al., 2008; Tolhuis et al., 2002).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
What the sources say
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In the paper
“Together, these studies demonstrate that stringent developmental regulation of a gene can be overcome through the manipulation of higher order chromatin structure”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“consistent with the idea that βh1-SA recruits the LCR towards the βh1-globin gene at the expense of the β-major gene.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > βh1-SA-mediated activation of embryonic globin gene expression in primary adult erythroblasts
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“demonstrating that embryonic globin gene activation was dependent on a long range LCR interaction.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“and by extension is dependent on chromatin looping.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > βh1-SA activation of βh1-globin expression is LCR-dependent
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 conclusion, βh1-SA mediated activation of βh1-globin transcription requires the LCR”
§ 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
“In sum, recruitment of the Ldb1 SA domain to the βh1-globin promoter is capable of substantially antagonizing the stringent developmental silencing mechanisms operational in definitive murine erythroid cells.”
§ 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
“Hence, manipulating chromatin loops might be a viable strategy to reverse the globin switch.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Therefore, it should be possible to activate any other similarly regulated nearby gene by producing an interaction between it and the active LCR.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
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In the paper
“Since the sum of γ-globin and β-globin transcripts remained similar vis-à-vis α-globin mRNA levels, this further supports the idea that GG1-SA functions via competition for the LCR.”
§ 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: passesA 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
“consistent with GG1-SA competitively reconfiguring looped contacts towards γ-globin promoter at the expense of the β-globin promoter.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > GG1-SA induces γ-globin promoter-LCR looping
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“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).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
What the sources say
- Not checked yetcites Deng et al., 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“confirming that the effects of βh1-SA are specific.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Results > βh1-SA mediated activation of an embryonic globin gene in adult erythroblasts
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In the paper
“indicating that in these experiments GG1-SA expression did not significantly affect overall erythroid maturation.”
§ 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
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“consistent with competition for long-range LCR activity.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“These results demonstrated that forced juxtaposition of an enhancer and promoter via chromatin looping can trigger gene activation”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
What the sources say
- Not checked yetcites Deng et al., 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“The present results indicate that the Ldb1 SA domain is also capable of forging a chromatin interaction between the LCR and globin genes that represent earlier stages of development, leading to marked increases in transcription.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Our findings support that chromatin looping plays an essential role in controlling globin switching, and suggest a possible strategy for the treatment of those hemoglobinopathies that would benefit from the activation of alternative β-like globin genes.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Several lines of evidence strongly support loop formation as the underlying mechanism of transcriptional activation.”
- Also stated in: § Discussion · boosted
“Therefore, in aggregate these data strongly support that Ldb1 SA-induced transcriptional activation is a functional consequence of its impact on the higher order chromatin organization within the β-globin locus.”
§ 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 · boosted
None of the sources cited for this claim have been checked yet.
In the paper
“Patients affected by sickle cell anemia and β-thalassemia experience a milder course of the disease if they express elevated levels of fetal hemoglobin in adulthood (Platt et al., 1994; Weatherall, 2001).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Among these, arguably the most powerful one is nucleated by Bcl11a (Sankaran et al., 2008; 2009) which does not bind directly to promoters of the silenced human fetal globin genes but seems to repress them via a mechanism involving higher order chromatin looping (Kiefer et al., 2011; Xu et al., 2010).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
What the sources say
- Not matchedcites Sankaran et al., 2008; 2009
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked yetcites Kiefer et al., 2011 source
- Not matchedcites Xu et al., 2010
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Not matched
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
“and that such manipulations have the potential for therapeutic applications.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Introduction
Tests✓ Asserted: passes? Checkable: unclear✓ Load-bearing: passes✓ Based: passesIn the paper
“Exposure of developing human erythroid cells to in vitro culture conditions variably elevates basal fetal globin gene expression, suggesting that the human γ-globin genes are in a poised and therefore more responsive state when compared to the murine embryonic genes. (Fibach et al., 1993).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
What the sources say
- Not checked yetcites Fibach et al., 1993 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“This indicates that direct recruitment of the active LCR to the γ-globin genes can effectively override its developmental repression.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 summary, we have shown that forced long-range chromatin interactions can be used to reactivate a developmentally silenced gene.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesWhat the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Two of these produced sufficiently high ChIP signals with the desired specificity.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > EXPERIMENTAL PROCEDURES > Artificial Zinc Finger Design
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“When employed at a complex gene locus at which promoters compete for enhancer activity this strategy can lead to reciprocal reduction in the expression of alternate genes.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Therefore, manipulation of chromatin looping can in principle be applied for gene activation or repression at any gene that is controlled by a looped distal enhancer.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“This lends further support to the idea that spatial proximity is a key determinant of enhancer activity.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“This is consistent with a more stringent developmental repression within the murine environment (Sankaran et al., 2009).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
What the sources say
- Not checked yetcites Sankaran et al., 2009 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“Therefore, the newly imposed spatial constraint of the LCR also increases the likelihood for interaction with a nearby gene.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“In fact, such levels, if achieved at the fetal globin genes in vivo in human sickle cell anemia patients would be sufficient to ameliorate the clinical course of their disease (see also below) (Noguchi et al., 1988; Platt et al., 1991).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“The reduction in adult β-globin expression might be an added therapeutic benefit since diminished synthesis of defective β-globin chains, as occurs in sickle cell anemia, would further improve the ratio of γ-globin chains available to pair with the α-globin chains.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“As a corollary, it is plausible that regulation of chromatin looping might also underlie the function of factors normally involved in globin gene switching.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Exposure of developing human erythroid cells to in vitro culture conditions variably elevates basal fetal globin gene expression, suggesting that the human γ-globin genes are in a poised and therefore more responsive state when compared to the murine embryonic genes. (Fibach et al., 1993).”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
What the sources say
- Not checked yetcites Fibach et al., 1993 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Hence GG1-SA might act in an environment that is more favorable for further activation.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“which may be a more easily achievable and sustainable compared to what would be required if expressing a γ-globin transgene.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Therefore, it is expected that in a therapeutic setting fewer dysfunctional erythroid cells would remain to contribute to disease.”
§ Reactivation of developmentally silenced globin genes by forced chromatin looping > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: 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).
- 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
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
“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
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
“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
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
“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
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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
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)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
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)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
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
Cites
Mortality in sickle cell disease. Life expectancy and risk factors for early death
Platt, O. S., Brambilla, D. J., Rosse, W. F., Milner, P. F., Castro, O., Steinberg, M. H., & Klug, P. P. (1994) · New England Journal of Medicine · doi:10.1056/nejm199406093302303 · Cited by 3,320 · cited 1×
“Patients affected by sickle cell anemia and b-thalassemia experience a milder course of the disease if they express elevated levels of fetal hemoglobin in adulthood (Platt et al., 1994; Weatherall, 2001).”
BackgroundPain in Sickle Cell Disease: Rates and Risk Factors
Platt, O. S., Thorington, B. D., Brambilla, D. J., Milner, P. F., Rosse, W. F., Vichinsky, E., & Kinney, T. R. (1991) · New England Journal of Medicine · doi:10.1056/nejm199107043250103 · Cited by 1,546
Looping and Interaction between Hypersensitive Sites in the Active β-globin Locus
Tolhuis, B., Palstra, R.-J., Splinter, E., Grosveld, F., & de Laat, W. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00781-5 · Cited by 1,344
RNA-guided gene activation by CRISPR-Cas9-based transcription factors
Perez-Pinera, P., Kocak, D. D., Vockley, C. M., Adler, A. F., Kabadi, A. M., Polstein, L. R., Thakore, P. I., Glass, K. A., Ousterout, D. G., Leong, K. W., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2600 · Cited by 1,328
Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-Specific Repressor BCL11A
Sankaran, V. G., Menne, T. F., Xu, J., Akie, T. E., Lettre, G., Van Handel, B., Mikkola, H. K. A., Hirschhorn, J. N., Cantor, A. B., & Orkin, S. H. (2008) · Science · doi:10.1126/science.1165409 · Cited by 919
Deng, W., Lee, J., Wang, H., Miller, J., Reik, A., Gregory, P. D., Dean, A., & Blobel, G. A. (2012) · Cell · doi:10.1016/j.cell.2012.03.051 · Cited by 734 · cited 13×
“The ZFs targeting HS2 of the mouse LCR and the human g-globin promoters have been described previously (Deng et al., 2012; Gräslund et al., 2005).”
BackgroundMethodInfluentialSelf-citationQuantitative analysis of chromosome conformation capture assays (3C-qPCR)
Hagège, H., Klous, P., Braem, C., Splinter, E., Dekker, J., Cathala, G., de Laat, W., & Forné, T. (2007) · Nature Protocols · doi:10.1038/nprot.2007.243 · Cited by 720 · cited 2×
“Chromosome Conformation Capture 3C assays were performed as described (Hagège et al., 2007) with the following modifications.”
MethodPhenotype-genotype relationships in monogenic disease: lessons from the thalassaemias
Weatherall, D. J. (2001) · Nature Reviews Genetics · doi:10.1038/35066048 · Cited by 692
Long-range chromatin regulatory interactions in vivo
Carter, D., Chakalova, L., Osborne, C. S., Dai, Y.-F., & Fraser, P. (2002) · Nature Genetics · doi:10.1038/ng1051 · Cited by 663
An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level
Bauer, D. E., Kamran, S. C., Lessard, S., Xu, J., Fujiwara, Y., Lin, C., Shao, Z., Canver, M. C., Smith, E. C., Pinello, L., et al. (2013) · Science · doi:10.1126/science.1242088 · Cited by 653
Flagged first, then by citations
1 of the 55 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Hilton, I. B., D’Ippolito, A. M., Vockley, C. M., Thakore, P. I., Crawford, G. E., Reddy, T. E., & Gersbach, C. A. (2015) · Nature Biotechnology · doi:10.1038/nbt.3199 · Cited by 1,931
The CRISPR tool kit for genome editing and beyond
Adli, M. (2018) · Nature Communications · doi:10.1038/s41467-018-04252-2 · Cited by 1,545
Multiscale 3D Genome Rewiring during Mouse Neural Development
Bonev, B., Mendelson Cohen, N., Szabo, Q., Fritsch, L., Papadopoulos, G. L., Lubling, Y., Xu, X., Lv, X., Hugnot, J.-P., Tanay, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.043 · Cited by 1,338
Organization and function of the 3D genome
Bonev, B., & Cavalli, G. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.112 · Cited by 1,174
Long-range enhancer–promoter contacts in gene expression control
Schoenfelder, S., & Fraser, P. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0128-0 · Cited by 1,102
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
About these checks
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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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