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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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.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 33 cited sources checked · 0 supported · 0 flagged
- Findingown data
Total hemoglobin production remained unchanged between controls and GG1-SA containing cells.
“Importantly, total hemoglobin production remained unchanged between controls and GG1-SA containing cells (Figure 5B)”
Quote in the paperSubstantial claim - Findingown data
Loss of the LCR had no impact on basal level βh1-globin transcription.
“While the loss of the LCR had no impact on basal level βh1-globin transcription”
Quote in the paperSubstantial claim - Findingown data
GG1-SA expression led to a dramatic increase in the percentage of HbF compared to uninfected controls or GG1-Only.
“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).”
Quote in the paperSubstantial claim - Findingown data
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.
“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.”
Quote in the paperSubstantial claim - Findingown data
GG1-SA expressing cells produced γ-globin approximating 85% of total globin synthesis compared with ~25% in GFP negative cells.
“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).”
Quote in the paperSubstantial claim
- Findingown data
βh1-SA activated βh1-globin transcription by almost 800-fold compared to empty vector control.
“βh1-SA activated βh1-globin transcription by almost 800-fold compared to empty vector control (Figure 2B)”
Quote in the paperSubstantial claim - Findingown data
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).
“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).”
Quote in the paperSubstantial claim - Findingreasoning
Increases in embryonic or fetal globin gene expression were accompanied by a reciprocal decrease in adult β-globin expression.
“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.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingcitation
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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Deng et al., 2012 source
Not checked in the free run.
- Findingown data
The reciprocal alteration in fetal versus adult globin gene transcription was reflected in corresponding changes in contact frequencies with the LCR.
“The reciprocal alteration in fetal versus adult globin gene transcription was reflected in corresponding changes in contact frequencies with the LCR.”
Quote in the paperSubstantial claim - Findingown data
Adult hemoglobin levels (HbA and HbA2) declined markedly upon GG1-SA expression.
“Correspondingly, adult hemoglobin levels (HbA and HbA2) declined markedly.”
Quote in the paperSubstantial claim - Findingown data
Deletion of the LCR essentially abrogated the effects of the tethered Ldb1 SA domain.
“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.”
Quote in the paperSubstantial claim - Findingown data
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, at least partially reversing the developmental gene switch.
“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).”
Quote in the paperSubstantial claim - Findingown data
GG1-SA targeting was highly specific for the γ-globin promoters with little or no signal at the other globin promoters.
“GG1-SA targeting was highly specific for the γ-globin promoters with little or no signal at the other globin promoters (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
GG1-SA expression established a strong interaction between the LCR and the γ-globin genes that is absent in control cells.
“GG1-SA expression established a strong interaction between the LCR and the γ-globin genes that is absent in control cells (Figure 7).”
Quote in the paperSubstantial claim - Findingown data
GG1-SA induced a ~2.5-fold increase in γ-globin expression compared to GG1-Only and control populations.
“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).”
Quote in the paperSubstantial claim- Rests on an assumption: As erythroid cells undergo maturation, the ratio of fetal to adult hemoglobin declines.
- Findingown data
Loss of the LCR completely abrogated the induction of βh1-globin expression seen in wild type mice.
“it completely abrogated the induction of βh1-globin expression seen in the wild type mice (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
GG1-SA expression resulted in a marked reduction in β-globin transcription (13.5% vs. control and 18.1% vs. GG1-Only).
“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).”
Quote in the paperSubstantial claim- Rests on an assumption: As erythroid cells undergo maturation, the ratio of fetal to adult hemoglobin declines.
- Findingown data
βh1-SA activated βh1-globin transcription exceeding 30% of total β-globin synthesis.
“exceeding 30% of total β-globin synthesis (Figure 2C).”
Quote in the paperSubstantial claim - Findingown data
The βh1-SA activity was abrogated in erythroid cells from mice in which the LCR had been deleted.
“This activity was abrogated in erythroid cells from mice in which the LCR had been deleted”
Quote in the paperSubstantial claim - Findingown data
β-major expression was slightly reduced in both βh1-SA expressing populations.
“Importantly, β-major expression was slightly reduced in both βh1-SA expressing populations (Figure 2B,S2A)”
Quote in the paperNot a substantial claim - Findingown data
Interactions between the LCR and the adult globin genes (δ- and β-globin) were diminished upon GG1-SA expression.
“Additionally, interactions between the LCR and the adult globin genes (δ- and β-globin) were diminished”
Quote in the paperSubstantial claim - Findingown data
ChIP revealed specific binding of βh1-SA to the βh1-globin promoter but not the promoters of the other β-like globin genes.
“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).”
Quote in the paperSubstantial claim - Findingreasoning
Marked effects in fetal globin reactivation were achieved with relatively low levels of GG1-SA transgene expression (<1% of globin genes).
“Finally, marked effects in fetal globin reactivation were achieved with relatively low levels of GG1-SA transgene expression (<1% of globin genes)”
Quote in the paperSubstantial claim - Findingnone given
GG1-SA expression raised fetal globin expression in the vast majority of transduced cells.
“However, GG1-SA expression raised fetal globin expression in the vast majority of transduced cells.”
Quote in the paperSubstantial claim - Findingreasoning
εy-globin up-regulation was dependent on the LCR.
“Similar to βh1-globin, εy-globin up-regulation was dependent on the LCR.”
Quote in the paperSubstantial claim - Findingcitation
Tethering the SA domain did not activate murine embryonic genes to the same level as the human fetal genes.
“Tethering the SA domain did not activate murine embryonic genes to the same level as the human fetal genes.”
Quote in the paperNot a substantial claim - Premisecitation
In erythroid cells, the locus control region (LCR) is in physical proximity to the β-globin genes in a developmentally dynamic manner.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
Controlled manipulation of chromatin folding in the nucleus can be used as a strategy to modulate, positively or negatively, the transcription of designated genes.
“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.”
Quote in the paperSubstantial claim - Premisecitation
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).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Central to the mechanism of globin gene switching is the exclusive interaction between the LCR and globin gene promoters at distinct developmental stages.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Stringent developmental regulation of a gene can be overcome through the manipulation of higher order chromatin structure.
“Together, these studies demonstrate that stringent developmental regulation of a gene can be overcome through the manipulation of higher order chromatin structure”
Quote in the paperSubstantial claim - Interpretationown data
βh1-SA recruits the LCR towards the βh1-globin gene at the expense of the β-major gene.
“consistent with the idea that βh1-SA recruits the LCR towards the βh1-globin gene at the expense of the β-major gene.”
Quote in the paperSubstantial claim - Interpretationown data
Embryonic globin gene activation was dependent on a long range LCR interaction.
“demonstrating that embryonic globin gene activation was dependent on a long range LCR interaction.”
Quote in the paperSubstantial claim - Interpretationreasoning
βh1-SA mediated activation of βh1-globin transcription is dependent on chromatin looping.
“and by extension is dependent on chromatin looping.”
Quote in the paperSubstantial claim - Interpretationown data
βh1-SA mediated activation of βh1-globin transcription requires the LCR.
“In conclusion, βh1-SA mediated activation of βh1-globin transcription requires the LCR”
Quote in the paperSubstantial claim - Interpretationown data
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.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning
Manipulating chromatin loops might be a viable strategy to reverse the globin switch.
“Hence, manipulating chromatin loops might be a viable strategy to reverse the globin switch.”
Quote in the paperSubstantial claim - Interpretationreasoning
It should be possible to activate any other similarly regulated nearby gene by producing an interaction between it and the active LCR.
“Therefore, it should be possible to activate any other similarly regulated nearby gene by producing an interaction between it and the active LCR.”
Quote in the paperSubstantial claim - Interpretationown data
GG1-SA functions via competition for the LCR.
“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.”
Quote in the paperSubstantial claim - Interpretationown data
GG1-SA competitively reconfigures looped contacts towards the γ-globin promoter at the expense of the β-globin promoter.
“consistent with GG1-SA competitively reconfiguring looped contacts towards γ-globin promoter at the expense of the β-globin promoter.”
Quote in the paperSubstantial claim - Premisecitation
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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Deng et al., 2012 source
Not checked in the free run.
- Interpretationown data
The effects of βh1-SA are specific.
“confirming that the effects of βh1-SA are specific.”
Quote in the paperSubstantial claim - Interpretationown data
GG1-SA expression did not significantly affect overall erythroid maturation in these experiments.
“indicating that in these experiments GG1-SA expression did not significantly affect overall erythroid maturation.”
Quote in the paperSubstantial claim - Interpretationown data
The reciprocal decrease in adult β-globin expression is consistent with competition for long-range LCR activity.
“consistent with competition for long-range LCR activity.”
Quote in the paperSubstantial claim - Interpretationcitation
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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Deng et al., 2012 source
Not checked in the free run.
- Interpretationown data
The Ldb1 SA domain is capable of forging a chromatin interaction between the LCR and globin genes that represent earlier stages of development, leading to marked increases in transcription.
“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.”
Quote in the paperSubstantial claim - Interpretationown data
Chromatin looping plays an essential role in controlling globin switching.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning
Loop formation is the underlying mechanism of transcriptional activation by the tethered Ldb1 SA domain.
“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.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Premisecitation
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.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Bcl11a represses silenced human fetal globin genes via a mechanism involving higher order chromatin looping.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Sankaran et al., 2008; 2009
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Kiefer et al., 2011 source
Not checked in the free run.
- cites Xu et al., 2010
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
Manipulations of higher order chromatin structure have the potential for therapeutic applications.
“and that such manipulations have the potential for therapeutic applications.”
Quote in the paperNot a substantial claim - Premisecitation
Exposure of developing human erythroid cells to in vitro culture conditions variably elevates basal fetal globin gene expression.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fibach et al., 1993 source
Not checked in the free run.
- Interpretationown data
Direct recruitment of the active LCR to the γ-globin genes can effectively override its developmental repression.
“This indicates that direct recruitment of the active LCR to the γ-globin genes can effectively override its developmental repression.”
Quote in the paperSubstantial claim - Interpretationown data
Forced long-range chromatin interactions can be used to reactivate a developmentally silenced gene.
“In summary, we have shown that forced long-range chromatin interactions can be used to reactivate a developmentally silenced gene.”
Quote in the paperSubstantial claim - Study design and conductown data
Two of the five ZFs produced sufficiently high ChIP signals with the desired specificity.
“Two of these produced sufficiently high ChIP signals with the desired specificity.”
Quote in the paperSubstantial claim - Interpretationown data
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.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning
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.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning
Spatial proximity is a key determinant of enhancer activity.
“This lends further support to the idea that spatial proximity is a key determinant of enhancer activity.”
Quote in the paperSubstantial claim - Interpretationcitation
The lower activation of murine embryonic genes is consistent with a more stringent developmental repression within the murine environment.
“This is consistent with a more stringent developmental repression within the murine environment (Sankaran et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sankaran et al., 2009 source
Not checked in the free run.
- Interpretationown data
The newly imposed spatial constraint of the LCR increases the likelihood for interaction with a nearby gene.
“Therefore, the newly imposed spatial constraint of the LCR also increases the likelihood for interaction with a nearby gene.”
Quote in the paperSubstantial claim - Interpretationcitation
Such levels of βh1-globin expression, 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.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
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.
“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.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Regulation of chromatin looping might also underlie the function of factors normally involved in globin gene switching.
“As a corollary, it is plausible that regulation of chromatin looping might also underlie the function of factors normally involved in globin gene switching.”
Quote in the paperNot a substantial claim - Premisecitation
The human γ-globin genes are in a poised and therefore more responsive state when compared to the murine embryonic genes.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fibach et al., 1993 source
Not checked in the free run.
- Interpretationreasoning
GG1-SA might act in an environment that is more favorable for further activation.
“Hence GG1-SA might act in an environment that is more favorable for further activation.”
Quote in the paperNot a substantial claim - Interpretationown data
Low levels of GG1-SA transgene expression may be more easily achievable and sustainable compared to what would be required if expressing a γ-globin transgene.
“which may be a more easily achievable and sustainable compared to what would be required if expressing a γ-globin transgene.”
Quote in the paperSubstantial claim - Interpretationreasoning
In a therapeutic setting, fewer dysfunctional erythroid cells would remain to contribute to disease.
“Therefore, it is expected that in a therapeutic setting fewer dysfunctional erythroid cells would remain to contribute to disease.”
Quote in the paperSubstantial claim- 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).
- May combine two claims. 16
- Classified as probably not a substantial claim. 9
May combine two claims.
Findingown dataGG1-SA resulted in nearly pancellular HbF expression whereas GG1-Only triggered expression merely in a subset of cells.
“GG1-SA resulted in nearly pancellular HbF expression whereas GG1-Only triggered expression merely in a subset of cells (Figure 6)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGG1-SA expression strongly stimulated γ-globin promoter-LCR interactions with a concomitant decrease in β-globin-LCR contacts.
“Third, 3C experiments revealed that GG1-SA expression strongly stimulated γ-globin promoter-LCR interactions with a concomitant decrease in β-globin-LCR contacts.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataβh1-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.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPrimary 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.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataβh1-SA activated βh1-globin expression and also to some degree the expression of εy-globin, which resides closer to the LCR than βh1-globin.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEven 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.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn 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 proteins established an LCR-promoter loop similar to that observed in mature erythroid cells and stimulated transcription.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Deng et al., 2012
Not checked in the free run.
May combine two claims.
PremisecitationThe self-association (SA) domain of Ldb1 was sufficient for the activity of establishing an LCR-promoter loop and stimulating transcription.
“The self-association (SA) domain of Ldb1 was sufficient for this activity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Deng et al., 2012
Not checked in the free run.
May combine two claims.
Interpretationown dataGG1-SA strongly induces the expression of γ-globin with resulting loss in β-globin transcription.
“Together these results demonstrate that GG1-SA strongly induces the expression of γ-globin with resulting loss in β-globin transcription.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataGG1-SA potently induces HbF at distinct stages of erythroid differentiation and independent of stem cell source.
“Taken together, these results demonstrate potent induction of HbF by GG1-SA at distinct stages of erythroid differentiation and independent of stem cell source.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationGenomic proximity to the LCR correlates with the ability to compete for LCR activity in transgenic mice.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Bauchwitz and Costantini, 2000
Not checked in the free run.
- cites Hanscombe et al., 1991
Not checked in the free run.
- cites Peterson and Stamatoyannopoulos, 1993
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationIn primitive murine erythroid cells, the LCR loops to the embryonic β-globin gene promoters (εy and βh1), whereas in definitive erythroid cells, the LCR exclusively contacts the adult β-globin genes (β-major and β-minor) with the intervening embryonic globin genes looped out.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Palstra et al., 2003
Not checked in the free run.
May combine two claims.
Interpretationown dataTethering 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.
“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.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationSeveral transcription factors, including Klf1, GATA1, and its co-regulators Ldb1 and FOG1, have been implicated in loop formation at the β-globin locus.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Drissen, 2004
Not checked in the free run.
- cites Song et al., 2007
Not checked in the free run.
- cites Vakoc et al., 2005
Not checked in the free run.
May combine two claims.
Interpretationown dataThe tethered Ldb1 SA domain does not substitute for the LCR by simply enhancing promoter activity, but instead requires long-range LCR action.
“indicating that it does not substitute for the LCR by simply enhancing promoter activity, but instead requires long-range LCR action.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenFive ZFs were FLAG tagged and screened by anti-FLAG ChIP for in vivo binding to the βh1 promoter in G1E cells.
“Five ZFs were FLAG tagged and screened by anti-FLAG ChIP for in vivo binding to the βh1 promoter in G1E cells.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given3C signals were normalized to template standards generated from a locus-specific BAC and to 3C signals from the tubulin locus.
“The 3C signals were normalized to template standards generated from a locus-specific BAC and to 3C signals from the tubulin locus.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenCell purity was confirmed by post sort flow cytometry.
“Cell purity was confirmed by post sort flow cytometry.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationBcl11a does not detectably bind to the γ-globin gene promoters but appears to regulate the looped configuration of the locus.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Xu et al., 2010
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductreasoningTo eliminate variability between donor samples, interaction frequencies between the anchor fragment and the fragment encompassing the Gγ-globin gene or the β-globin from the GG1-SA sample of each donor were set to one.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenChosen ZF target sequences were within the DNase I hypersensitive region to facilitate access but avoid interference with known transcription factor binding sites.
“Chosen target sequences were within the DNase I hypersensitive region to facilitate access but avoid interference with known transcription factor binding sites.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe LCR is incapable of interacting with multiple globin promoters at once but instead contacts either the fetal or adult genes.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Enver et al., 1990
Not checked in the free run.
- cites Wijgerde et al., 1995
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductcitationThe βh1-globin zinc finger proteins were screened for DNA binding by ELISA assay in vitro.
“ZFs were assembled from two-finger units and screened for DNA binding by ELISA assay in vitro as described (Bartsevich et al., 2003).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bartsevich et al., 2003
Not checked in the free run.
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?
Ectopic tethering of LDB1 to chromatin is sufficient for loop formation, increased deposition of the enhancer mark H3K4me1 and transcriptional activation.
“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]
The Discussion reports that tethering the Ldb1 self-association domain increased γ-globin promoter–LCR contacts and activated transcription. Neither the cited passages nor searches for H3K4me1 and histone H3 lysine 4 monomethylation support the claimed increase in deposition of that enhancer mark. (LLM, conf=0.88)
Experimental — accuracy not yet measuredObservations support a model where dynamic chromatin looping from enhancer regions triggers gene activation.
“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
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- 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 · 2013: 1
- 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 › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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