The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index; 33 of the 42 sources its claims cite were checked for support.
Insulator dysfunction and oncogene activation in IDH mutant gliomas
Open accessAbstract
Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.
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52 Own result · 17 Own method · 13 Own interpretation · 10 Partly supported · 8 Supported · 4 No full text of the sources · 2 Supported so far · 1 No basis given · accuracy not yet measured
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In the paper
“Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Supportedcites [3] Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009) source
The Discussion states that mutant IDH1 catalyzes the conversion of α-ketoglutarate to 2HG and describes 2HG production as a result of IDH1 mutations. This supports the production claim attributed to this source; the supplied passages do not give page numbers. (LLM, conf=0.94)
- Supportedcites [4] Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010) source
The Introduction states that common IDH1/2 mutations acquire an enzymatic activity that produces 2HG. The Results section reports markedly elevated 2HG levels in cells expressing mutant IDH1 or IDH2 compared with the corresponding wild-type enzymes. Page numbers were not supplied. (LLM, conf=0.94)
- Supportedcites [5] Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011) source
The Introduction states that mutant IDH1 and IDH2 gain the ability to produce D-2-HG. The Results also report increased D-2-HG after expression of mutant IDH1 in human glioma cells. (LLM, conf=0.94)
- Supportedcites [6] Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012) source
The paper reports that cells expressing mutant IDH2 produced 2HG, whereas cells expressing wild-type IDH2 or a control vector did not (passage [3], labeled Abstract, Fig. 2a). This directly supports the attributed claim. (LLM, conf=0.95)
- Not checked — no full text of the sourcecites [7] Cairns, R. A. & Mak, T. W. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Dis. 3, 730–741 (2013) source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP)10,11, though the functional significance of this altered epigenetic state remains unclear.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Partly supportedcites [10] Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010) sourceExperimental — accuracy not yet measured
The Results sections report a strong association between IDH1 mutation and G-CIMP in gliomas. But in an independent set, only 35 of 48 IDH1-mutant tumors (72.9%) were G-CIMP-positive, and the paper observed no IDH2 mutations in its TCGA set. The claim is therefore broader than the paper’s finding: not all IDH1-mutant gliomas showed the phenotype, and it does not establish the association for IDH mutations generally. (LLM, conf=0.84)
- Supportedcites [11] Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012) source
The Abstract states that IDH mutation establishes glioma CIMP (G-CIMP). The tumour-sequencing passage reports that 49 of 50 G-CIMP-positive tumours had an IDH1 or IDH2 mutation, while none of the G-CIMP-negative tumours did. The citation supports the G-CIMP clause; the sentence’s separate comment about functional significance is not attributed to it. (LLM, conf=0.94)
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In the paper
“Consistent with prior studies16, we found that genes in the same domain correlate across samples, but that genes separated by a boundary show lower correlation (Fig. 1e).”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Partly supportedcites [16] Nora, E. P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012) sourceExperimental — accuracy not yet measured
The transcriptome-analysis passage (labeled Abstract, Fig. 4b) reports that genes within the same TAD had more correlated expression profiles than genes in different domains. But it measured 17 time points during female mouse embryonic stem-cell differentiation, not correlations across normal brain samples. (LLM, conf=0.88)
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In the paper
“Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Partly supportedcites [3] Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009) sourceExperimental — accuracy not yet measured
The section “Mutant IDH1 directly converts αKG to 2HG” confirms that mutant IDH1 produces 2HG. The Discussion suggests that 2HG may inhibit αKG-dependent prolyl hydroxylases, but presents this as a possibility, not an established effect. Our copy does not identify TET 5-methylcytosine hydroxylases as targets. (LLM, conf=0.88)
- Partly supportedcites [4] Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010) sourceExperimental — accuracy not yet measured
The Results section (page unavailable) identifies TET enzymes as iron-dependent 5-methylcytosine hydroxylases and shows that mutant IDH inhibits TET2-mediated hydroxylation. The paper proposes 2-HG as the mechanism, but does not establish interference with the TET family as a whole or with other iron-dependent hydroxylases; the Discussion treats effects on other enzyme families as a possibility for future study. (LLM, conf=0.83)
- Supportedcites [5] Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011) source
The Results section, “2-HG Inhibits the Activity of TET 5-Methylcytosine Hydroxylases” (page not provided), reports that 2-HG inhibits TET1 and TET2 in assays of 5-methylcytosine hydroxylation. The Enzymatic Assays section includes an iron salt in the TET reaction mixture, consistent with the description of these hydroxylases as iron-dependent. (LLM, conf=0.92)
- Partly supportedcites [6] Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012) sourceExperimental — accuracy not yet measured
The paper’s Abstract (page unavailable) states that mutant IDH produces 2HG, reports mutant IDH-induced inhibition of the α-ketoglutarate-dependent enzyme TET2, and shows that 2HG inhibits a histone demethylase. It does not explicitly establish inhibition of the TET family as a whole or describe these enzymes as iron-dependent hydroxylases. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [7] Cairns, R. A. & Mak, T. W. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Dis. 3, 730–741 (2013) source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Our ChIP-seq data confirm that this boundary contains a strong CTCF binding site over a canonical CTCF motif with a CpG dinucleotide in a position previously linked to methylation-sensitivity25 (Fig. 3b).”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Supportedcites [25] Wang, H. et al. Widespread plasticity in CTCF occupancy linked to DNA methylation. Genome Res. 22, 1680–1688 (2012) source
The Results section (‘Variable CTCF occupancy linked to CpG methylation’) reports that CpGs at particular positions in the CTCF recognition sequence are associated with methylation-sensitive occupancy, and that methylation at position 1 has been shown to inhibit CTCF binding in vitro. The citation supports the prior link to methylation sensitivity; the citing authors attribute the strong binding at their particular boundary to their own ChIP-seq data. (LLM, conf=0.92)
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In the paper
“Nonetheless, IDH mutant gliomas strongly express PDGFRA (Fig. 2b), and share the proneural transcriptional program characteristic of PDGFRA-amplified tumors23,24.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Partly supportedcites [23] Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013) sourceExperimental — accuracy not yet measured
In Results, under “Molecular subclasses defined by global mRNA expression and DNA Methylation” (page unavailable), the paper describes G-CIMP and non-G-CIMP proneural glioblastomas as transcriptomically similar and associates PDGFRA amplification with the non-G-CIMP proneural subgroup. It reports that all IDH1-mutant cases had the G-CIMP pattern. These findings support the shared proneural program in the glioblastomas studied, but do not establish it for IDH-mutant gliomas more broadly. (LLM, conf=0.82)
- Partly supportedcites [24] Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1 . Cancer Cell 17, 98–110 (2010) sourceExperimental — accuracy not yet measured
In Results > Functional Annotation of Subtypes (page unavailable), the paper reports that 11 of 12 IDH1 mutations occurred in the Proneural class, which was also enriched for PDGFRA amplification and had a proneural expression signature. This supports the shared-program claim for the glioblastomas studied, but not its extension to IDH-mutant gliomas generally. (LLM, conf=0.85)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Consistent with prior studies16, we found that genes in the same domain correlate across samples, but that genes separated by a boundary show lower correlation (Fig. 1e).”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Partly supportedcites [16] Nora, E. P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012) sourceExperimental — accuracy not yet measured
The passage on gene expression dynamics during early differentiation reports that genes within the same TAD had more correlated expression profiles than genes in different domains. It measured female mouse embryonic stem cells over a differentiation time course, not normal brain samples, so it does not support that setting. (LLM, conf=0.88)
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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
“Here we show that IDH mutant gliomas exhibit hyper-methylation at CTCF binding sites, compromising binding of this methylation-sensitive insulator protein.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and down-regulates PDGFRA.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We found that these loci have higher GC content, and exhibit significantly higher levels of DNA methylation in IDH mutant gliomas, relative to IDH wildtype (Fig. 1c–d).”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Genomic alterations that remove CTCF-associated boundaries allow aberrant enhancer-gene interactions and alter gene expression17.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Supportedcites [17] Lupiáñez, D. G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161, 1012–1025 (2015) source
The Discussion section “Boundary structures are important for TAD integrity” identifies CTCF-binding clusters at the tested boundaries and reports that preserving those boundaries prevented ectopic interactions and gene misexpression. “A framework for interpreting human structural variation” states that deletions removing a boundary permit enhancer contact with genes outside the TAD, causing misexpression. (LLM, conf=0.93)
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In the paper
“TET enzymes catalyze a key step in the removal of DNA methylation8,9.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Supportedcites [8] Pastor, W. A., Aravind, L. & Rao, A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nature Rev. Mol. Cell Biol. 14, 341–356 (2013) source
The passage headed “TET-mediated DNA demethylation: mechanisms” describes TET oxidation of 5-methylcytosine as a step in pathways that ultimately replace it with cytosine. The “Active DNA demethylation through DNA repair” passage likewise explains how TET oxidation products are removed and replaced with cytosine. Page numbers were not supplied. (LLM, conf=0.93)
- Supportedcites [9] Kohli, R. M. & Zhang, Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502, 472–479 (2013) source
The Abstract states that TET enzymes oxidize 5-methylcytosine, advancing the understanding of DNA demethylation. The passage headed “BOX 1. Roles of 5hmC in DNA demethylation” describes TET-mediated oxidation as a step in pathways that return methylated cytosine to unmodified cytosine. (LLM, conf=0.94)
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Probably not a substantial claim.
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In the paper
“Recent studies have solidified the role of the CTCF insulator protein in creating chromatin loops and boundaries that partition such domains15.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Supportedcites [15] Rao, S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014) source
The Results section reports that most loop anchors bind CTCF and that many loops demarcate domains. The Discussion says loops often demarcate domains and discusses the mechanism by which CTCF and cohesin form loops, supporting the citing sentence’s broad paraphrase. (LLM, conf=0.87)
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Probably not a substantial claim.
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In the paper
“Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas1,2.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Partly supportedcites [1] Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008) sourceExperimental — accuracy not yet measured
The ‘High-frequency alterations of IDH1 in GBM’ section links IDH1 mutations to secondary GBM and substantially longer survival, supporting their clinical and prognostic relevance. The Discussion calls an activating effect a speculation and says further analysis is needed to determine the effect on enzyme activity. The paper does not establish that these mutations increase enzyme activity or are initiating events, and its findings concern GBM rather than gliomas broadly. (LLM, conf=0.90)
- Partly supportedcites [2] The Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015) sourceExperimental — accuracy not yet measured
The Results (Mutational Landscape of Lower-Grade Gliomas; page not provided) suggest that IDH mutation is an initial event in molecular progression. The Results (Clinical Characteristics and Outcomes; page not provided) and Discussion show that IDH status, together with 1p/19q status, distinguishes groups with different clinical outcomes. Our copy does not characterize the IDH mutations as gain-of-function or establish increased enzyme activity, and it presents the proposed sequence as a suggestion rather than a proven initiating event. (LLM, conf=0.86)
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“To control for copy number changes, we first called copy number profiles from input sequencing data using CNVnator37. We then removed all regions where at least one sample had a strong deletion (<0.25), and normalized by copy number.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Chromatin Immunoprecipitation
What the sources say
- Supportedcites [37] Abyzov, A., Urban, A. E., Snyder, M. & Gerstein, M. CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 21, 974–984 (2011) source
The Discussion describes CNVnator as a method for discovering copy-number variation from sequencing read depth. The citation is attached to the use of CNVnator to call copy-number profiles; the deletion threshold and subsequent normalization are the citing authors’ own steps, not claims attributed to this source. (LLM, conf=0.93)
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Probably not a substantial claim. It may state two separate claims as one.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“FIP1L1 encodes an RNA processing protein that is constitutively expressed in neural tissues, and particularly active in oligodendrocyte precursors, a putative glioma cell-of-origin22 (Extended Data Fig. 2a).”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Supportedcites [22] Sturm, D. et al. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nature Rev. Cancer 14, 92–107 (2014) source
Citation 22 is attached to the description of oligodendrocyte precursors as a putative glioma cell of origin. In the Introduction, under “The cells of origin of glioblastoma” (page unavailable), the review says OPCs can be considered cells of origin for Nf1- and Trp53-mutant glioblastoma. (LLM, conf=0.91)
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
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In the paper
“Although PDGFRA is a frequent target of genomic amplification and gain-of-function mutations in glioblastoma (15%), such alterations are rare in IDH mutant tumors23,24.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Partly supportedcites [23] Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013) sourceExperimental — accuracy not yet measured
The Results section on molecular subclasses associates PDGFRA amplification with the non-G-CIMP+ proneural subgroup and describes concurrent amplification in a group predominantly lacking IDH1 mutations. The Results section on somatic alterations also finds IDH1 mutations more prevalent in GBM without RTK alterations. These findings support the direction of the amplification claim in GBM, but the cited passages do not establish that PDGFRA gain-of-function mutations are rare in IDH-mutant tumors. (LLM, conf=0.84)
- Partly supportedcites [24] Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1 . Cancer Cell 17, 98–110 (2010) sourceExperimental — accuracy not yet measured
The Results (Functional Annotation of Subtypes; page not available) say that most IDH1-mutant samples did not have a PDGFRA abnormality, supporting limited overlap in the glioblastomas studied. They do not establish that these alterations are rare across IDH-mutant tumors generally, or identify the observed PDGFRA mutations as gain-of-function. (LLM, conf=0.84)
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Genes in top scoring domains include PDGFRA (p<10−21), an established glioma oncogene22, and other candidate regulators of gliomagenesis (Table S1).”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Supportedcites [22] Sturm, D. et al. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nature Rev. Cancer 14, 92–107 (2014) source
The Structural variations in glioblastoma section reports recurrent PDGFRA amplification in adult and paediatric glioblastoma and describes it as a suggested key oncogenic event in diffuse intrinsic pontine glioma. This supports the citing sentence’s characterization of PDGFRA as an established glioma oncogene. (LLM, conf=0.91)
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Probably not a substantial claim.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Insulator dysfunction may also be accompanied by promoter silencing events28,29, and by alterations to other pathways affected by 2-HG7,30.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Supportedcites [28] Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome – biological and translational implications. Nature Rev. Cancer 11, 726–734 (2011) source
The citation to this paper is attached to “promoter silencing events,” not to the separate clause about other pathways affected by 2-HG. The “Promoter CpG island DNA hypermethylation” section reports that abnormal promoter methylation in cancer stabilizes transcriptional repression and causes loss of gene function. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [29] Costello, J. F., Berger, M. S., Huang, H. S. & Cavenee, W. K. Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation. Cancer Res. 56, 2405–2410 (1996)
- Not checked — no full text of the sourcecites [7] Cairns, R. A. & Mak, T. W. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Dis. 3, 730–741 (2013) source
- Supportedcites [30] Koivunen, P. et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484–488 (2012) source
This source is cited for the second clause, concerning other pathways affected by 2-HG, not for promoter silencing. In the supplied passages labeled Abstract, the paper identifies additional 2-HG targets, including TET2 and histone demethylases, and proposes that alterations in other 2-HG-affected enzymes may contribute to epigenetic changes. No page number is supplied. (LLM, conf=0.90)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“L1CAM (p<10−8), a regulator of the glioma stem cells and tumor growth39”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Genomic Scan for Deregulated Boundaries
What the sources say
- Supportedcites [39] Bao, S. et al. Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res. 68, 6043–6048 (2008) source
The Abstract reports that L1CAM knockdown inhibited growth in CD133+ glioma stem cells and suppressed tumor growth in glioma xenografts. The Results and Discussion section also describes L1CAM's role in maintaining CD133+ glioblastoma cell growth. The p-value appears to belong to the citing paper's analysis, not the claim attributed to this source. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Conversely, disruption of chromosomal topology and oncogene insulation may be more generally relevant to methylator phenotypes observed in colorectal and renal cell carcinomas, leukemia and other malignancies28.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Partly supportedcites [28] Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome – biological and translational implications. Nature Rev. Cancer 11, 726–734 (2011) sourceExperimental — accuracy not yet measured
In “Promoter CpG island DNA hypermethylation” (page unavailable), the paper describes methylation of an H19 insulator, loss of CTCF binding, and IGF2 activation in pre-neoplastic kidneys, with a link to colon cancer progression. In “Genetics meets epigenetics” (page unavailable), it discusses methylator phenotypes in gliomas and increased DNA hypermethylation in leukaemia. It does not link disrupted chromosomal topology or oncogene insulation to methylator phenotypes across the named cancers, and its kidney example concerns Wilms’ tumour rather than renal cell carcinoma. (LLM, conf=0.84)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Although PDGFRA is a frequent target of genomic amplification and gain-of-function mutations in glioblastoma (15%), such alterations are rare in IDH mutant tumors23,24.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Supportedcites [23] Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013) source
The Results section (‘The landscape of somatic alterations in glioblastoma’) reports PDGFRA alterations in 13.1% of glioblastomas and specifies focal amplification and/or mutation. That supports the paraphrase’s approximate 15% figure. (LLM, conf=0.92)
- Partly supportedcites [24] Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1 . Cancer Cell 17, 98–110 (2010) sourceExperimental — accuracy not yet measured
The Results (Functional Annotation of Subtypes; page unavailable) report PDGFRA amplification across glioblastoma subtypes and PDGFRA mutations in some Proneural tumors. They do not give an approximately 15% frequency or establish that the mutations are gain-of-function; the authors say the point mutations may disrupt ligand interaction. (LLM, conf=0.86)
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“BT142 G-CIMP status was confirmed by evaluating LINE methylation with the “Global DNA Methylation Assay – LINE-1″ kit (Active Motif), as described36, and by methylation-sensitive restriction digests.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Primary glioma specimens and gliomasphere models
What the sources say
- Partly supportedcites [36] Lai, R. K. et al. Genome-wide methylation analyses in glioblastoma multiforme. PLoS ONE 9, e89376 (2014) sourceExperimental — accuracy not yet measured
The “Levels of 5m-dC, 5hm-dC and LINE1 Methylation” section describes evaluating LINE-1 methylation, but by pyrosequencing, not with the named Active Motif kit. The cited paper does not report confirming BT142 G-CIMP status or using methylation-sensitive restriction digests for that purpose. No page number is available in our copy. (LLM, conf=0.82)
plainSingle case- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
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
“In support of an enhancer identity, the element is enriched for H3 lysine 4 mono-methylation (H3K4me1), but lacks H3K4me3, and contains conserved motifs bound by the glioma master transcription factors, OLIG2 and SOX2.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
plain- Asserted: passes — The authors put it forward as true.
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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
“This analysis highlighted 203 domain boundaries (Fig. 2a; Table S1; see Methods).”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“This is associated with reduced CTCF binding and a global deregulation of boundary elements that partition topological domains.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“Consistently, 3C reveals a strong interaction between FIP1L1 enhancer and PDGFRA promoter that is specific to the mutant line (Fig. 3i), and PDGFRA is highly expressed.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The human genome is organized into topological domains that represent discrete structural and regulatory units12.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Not checked — no full text of the sourcecites [12] Bickmore, W. A. & van Steensel, B. Genome architecture: domain organization of interphase chromosomes. Cell 152, 1270–1284 (2013) source
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
“Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results directly implicate DNA hyper-methylation in compromising CTCF binding, boundary function and oncogene insulation in IDH mutant tumors.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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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
“Cultures were confirmed to be mycoplasma-free via PCR methods.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Primary glioma specimens and gliomasphere models
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“CHD4 (p<10−32), a driver of glioblastoma tumor initiation38”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Genomic Scan for Deregulated Boundaries
What the sources say
- Not checked — no full text of the sourcecites [38] Chudnovsky, Y. et al. ZFHX4 interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state. Cell Rep. 6, 313–324 (2014) source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Notably, CTCF knock-down has been shown to increase cross-boundary interactions and decrease intra-domain interactions21.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
What the sources say
- Not checked — no full text of the sourcecites [21] Zuin, J. et al. Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc. Natl Acad. Sci. USA 111, 996–1001 (2014) source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It 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 ensure robustness to noise from lowly expressed genes, we first filtered out 6,476 genes expressed < 1 TPM in more than half of the samples (keeping 14,055 genes).”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Genomic Scan for Deregulated Boundaries
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably 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
“Data was normalized across days using an ATP standard curve.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Cell Growth Assay
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
“We conservatively estimate that CTCF motif disruption causes a ~3-fold increase in PDGFRA expression, given that DNA level analysis indicates that <50% of insulator CRISPR cells were successfully edited.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It 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
“Sonication of tumor specimens and gliomaspheres was calibrated such that DNA was sheared to between 400bp and 2000bp.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Chromatin Immunoprecipitation
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
“Single live cells were selected for analysis via side and forward scatter, and viable cells were selected by lack of an unstained channel (APC) autofluorescence.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > PDGFRA Flow Cytometry
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. 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 conclusion, we present a novel epigenetic mechanism by which gain-of-function IDH mutations induce PDGFRA expression and thereby promote fitness in a subset of gliomas.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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It 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 account for batch effects and difference in ChIP efficiency, we quantile normalized each dataset.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Chromatin Immunoprecipitation
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably 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
“To ensure robustness to cell type-specific boundaries, we repeated the analysis with GM12878, K562 and NHEK defined boundaries.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Genomic Scan for Deregulated Boundaries
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
“In order to avoid possible saturation, reads were downsampled to 5% reads collapsed as PCR duplicates, or 5 million fragments.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Chromatin Immunoprecipitation
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
“To ensure robustness, we also repeated the analysis using boundaries defined from HiC data for K562 and NHEK.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Cross-Boundary and Intra-Domain Gene Pair Correlation Analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
“PCR signal from tumor and gliomasphere 3C was normalized to digestion efficiency and BAC primer signal.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Chromatin Conformation Capture (3C)
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
“We confirmed IDH1 mutant status of GSC119 by RNA-seq (82 out of 148 reads overlapping the relevant position in the transcript correspond the mutant allele).”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Primary glioma specimens and gliomasphere models
plainSingle case- Asserted: passes — The authors put it forward as true.
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Probably 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
“Normalization was also verified by β-actin, F: 5′-AGA AAA TCT GGC ACC ACA CC -3′, R: 5′-AGA GGC GTA CAG GGA TAG CA -3′.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > PDGFRA Quantitative PCR
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably 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
“For sequence analysis, identical reads were collapsed to a single paired-end read in order to avoid PCR duplicates.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Chromatin Immunoprecipitation
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
“All samples were acquired with Institutional Review Board approval, and were deidentified prior to receipt.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Primary glioma specimens and gliomasphere models
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It 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
“For correlation analysis, patients with copy number variation in either gene were excluded from the analysis to control for effects of co-amplification.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > TCGA Correlation and Outcome Analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably 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
“The observation that genetic disruption of this CTCF boundary element induces PDGFRA expression and enhances proliferation provides strong support for our model that epigenetic disruption of this element offers similar growth advantage to IDH mutant gliomas.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Although disruption of this single boundary confers a growth advantage, it is unlikely to be the only mediator of IDH mutations in gliomas.”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The functional importance of the altered epigenetic state in IDH mutant gliomas is not yet known.
“though the functional significance of this altered epigenetic state remains unclear”
The authors state this as an assumption.
The CRISPR-induced deletion within the CTCF motif disrupts CTCF binding.
“contain a deletion within the CTCF motif expected to disrupt binding”
The paper relies on this without support.
The contact domains and boundaries defined in the cell lines used (IMR90, GM12878, K562, NHEK) are representative of those in glioma tumors.
“Contact domains of IMR90, GM12878, K562 and NHEK cells were obtained from published HiC data15.”
The paper relies on this without support.
CTCF binding sites in IDH wild-type tumors mark domain boundaries.
“Gene pairs were considered to span a boundary if they were assigned to different domains in both GM12878 and IMR90, and separated by a CTCF binding site in IDH wild type tumors.”
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?
In the citing paper
“These include mutations in DNA methylases and demethylases, histones 144 and histone modifiers, and genes involved in chromatin remodelling and chromosome architecture, but also metabolic genes such as IDH1 and IDH2 that affect histone and DNA methylation 57 and might perturb 3D genome architecture 145 (Fig. 4b).”
From Advances in epigenetics link genetics to the environment and disease (2019) · cites this paper as [145]
In the citing paper
“Inhibition of TET2 promotes leukemic transformation and is also suspected of playing a role in IDH mutant gliomas (Flavahan et al., 2016; Losman and Kaelin, 2013).”
From Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma (2018) · cites this paper as Flavahan et al., 2016
In the citing paper
“Mutations in IDH1 and IDH2 are mutually exclusive in AML, and IDH1/2 mutations induce cytosine hypermethylation and inhibit TET2-mediated 5-hydroxymethylation 95,96 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [96]
In the citing paper
“In one well characterized example, aberrant gain of 5mC at the binding site of insulator protein CCCTC-binding factor (CTCF) is observed in the Igf2/H19 locus in Beckwith-Wiedemann (fetal overgrowth) syndrome, and in the PDGFRA locus of IDH mutant gliomas (8, 9).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [9]
In the citing paper
“In both cases, hypermethylation of the binding site prevents CTCF binding and results in the disruption of chromatin topological domains leading to ectopic enhancer-promoter interactions.”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [9]
In the citing paper
“IDH mutant gliomas have been shown to exhibit hypermethylation at CTCF binding sites, which leads to a reduction in CTCF binding”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [117]
In the citing paper
“loss of CTCF in topologically associated domains removed the domain boundary and caused aberrant gene activation117.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [117]
In the citing paper
“Therefore, the dysregulation of chromatin looping may be causally related to carcinogenesis (Extended Data Fig. 7a) 31,32.”
From The structural basis for cohesin–CTCF-anchored loops (2020) · cites this paper as [32]
In the citing paper
“For example, modest increases in the expression of receptor tyrosine kinase genes can have meaningful effects on cell proliferation (Flavahan et al., 2016).”
From Cohesin Loss Eliminates All Loop Domains (2017) · cites this paper as Flavahan et al., 2016
In the citing paper
“Moreover, amplifications and rare mutations of the platelet-derived growth factor receptor alpha gene (PDGFRA) often co-occur with H3.3K27M and TP53 mutations, indicating a potential role of this receptor in tumorigenesis”
From H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas (2017) · cites this paper as Flavahan et al., 2016
In the citing paper
“While genetic perturbation of CTCF binding has been shown to result in misregulation of gene expression in various cell lines and cancer9–11,28”
From Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (2017) · cites this paper as [9]
In the citing paper
“Boundary disruption has recently been linked to cancer and diseases of limb development (Flavahan et al., 2016; Hnisz et al., 2016; Lupianez et al., 2015)”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Flavahan et al., 2016
In the citing paper
“Recent high-resolution Chromosome-Conformation-Capture sequencing studies have revealed that TAD boundaries are perturbed in rare human limb malformation diseases (Lupianez et al., 2015) and certain types of cancers (Flavahan et al., 2016; Hnisz et al., 2016), leading to enhancer miswiring and pathogenic disruption of gene expression.”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Flavahan et al., 2016
In the citing paper
“Domain insulation has been shown to be important for gene expression and physiology (Flavahan et al., 2016, Lupiáñez et al., 2015).”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Flavahan et al., 2016
In the citing paper
“Chromatin insulation occurs at multiple levels and leads to a hierarchical 3D nuclear organization, whereby smaller, less insulated regions (called also sub-TADs [Flavahan et al., 2016, Phillips-Cremins et al., 2013] or contact domains [Rao et al., 2014]) are nested inside TADs, which are usually bigger and more strongly insulated (Dixon et al., 2012, Nora et al., 2012, Sexton et al., 2012).”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Flavahan et al., 2016
In the citing paper
“Several other studies have reported the deregulation of chromatin folding structures in different cancer types11,15,16.”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [16]
In the citing paper
“Accordingly, deletion of a boundary between two TADs causes ectopic contacts between previously insulated loci3 and can cause aberrant gene expression through improper enhancer-promoter contact.27,28”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [27]
In the citing paper
“Silent proto-oncogenes typically occur within insulated neighborhoods and genetic modification of the neighborhood loop anchors can cause activation of these oncogenes (Flavahan et al., 2016; Hnisz et al., 2016).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Flavahan et al., 2016
In the citing paper
“Somatic mutations occur frequently and recurrently in the loop anchors of oncogene-containing Insulated neighborhoods in a variety of cancer cells (Figure 2E).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Flavahan et al., 2016
In the citing paper
“In a dozen loci and in multiple cell types, CRISPR/Cas9 deletion of CTCF binding sites at the anchors of insulated neighborhoods have been shown to produce changes in the expression of genes within the neighborhoods and immediately adjacent to the deleted neighborhood boundary.”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Flavahan et al., 2016
In the citing paper
“These observations are consistent with the idea that mutations that alter the loop anchor sites of oncogene-containing insulated neighborhoods make an important contribution to the misregulation of gene expression that is inherent to the cancer state (Flavahan et al., 2016; Hnisz et al., 2016; Katainen et al., 2015).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Flavahan et al., 2016
In the citing paper
“DNA hypermethylation occurs in some cancer cells, and tumor-specific DNA methylation has recently been implicated in the disruption of CTCF binding, alteration of chromosome structure and dysregulation of oncogene expression (Flavahan et al., 2016).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Flavahan et al., 2016
In the citing paper
“genome-wide, high-resolution understanding of chromosome cell-cycle dynamics11 is still limited by current technologies”
From Cell-cycle dynamics of chromosomal organization at single-cell resolution (2017) · cites this paper as [10]
In the citing paper
“In addition to CD4+ T cells, an unexpected role for L-2-HG in the promotion of tumour killing acting via CD8+ T cells, cytotoxic T lymphocytes important for anti-tumour immunity, has emerged149.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [149]
In the citing paper
“Accumulation of L-2-HG altered CD8+ T cell differentiation through modulation of both the histone and DNA methylation landscape of the cell, and also via HIF stability149.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [149]
In the citing paper
“Interestingly, Tyrakis and colleagues (2016) observed a dramatic increase in L-2-HG levels, reaching up to 1.5 mM, in response to T-cell receptor triggering in mouse CD8+ T cells149.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [149]
In the citing paper
“Furthermore, exogenous treatment of CD8+ T cells with L-2-HG greatly enhanced the in vivo proliferation, persistence and anti-tumour capacity of adoptively transferred CD8+ T cells149.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [149]
In the citing paper
“Mechanistically, HIF-1α stabilisation induced LDHA expression and activity, which promiscuously converted glutamine-derived α-KG to L-2-HG149.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [149]
In the citing paper
“This increase occurred under normoxic conditions and was dependent on HIF-1α stabilisation149.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [149]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
“In all six cell types examined, PDGFRA and FIP1L1 reside in distinct domains, separated by one CTCF-anchored constitutive boundary (Fig. 3a, Extended Data Fig. 3).”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > HiC Data Analysis and Visualization
“5 kb resolution intra-chromosomal contact scores for Chromosome 4 for the cell lines IMR90, NHEK, KBM7, K562, HUVEC, HMEC, and GM12878 were filtered to the region between 53,700kb and 55,400kb.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Methods and Materials > Cross-Boundary and Intra-Domain Gene Pair Correlation Analysis
“In Figure 1e, this difference in correlations is plotted against the significance of this difference (estimated by Fisher z-transformation).”
§ Insulator dysfunction and oncogene activation in IDH mutant gliomas > Abstract
“Consistent with prior studies16, we found that genes in the same domain correlate across samples, but that genes separated by a boundary show lower correlation (Fig. 1e).”
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The impact of DNA methylation on CTCF-mediated 3D genome organization
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BackgroundNonlinear control of transcription through enhancer-promoter interactions
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“Furthermore, Flavahan et al demonstrated that increased DNA methylation could prevent CTCF binding and interfere with the interaction of topological domains in gliomas (73).”
BackgroundMulti-scale signaling and tumor evolution in high-grade gliomas
Liu, J., Cao, S., Imbach, K. J., Gritsenko, M. A., Lih, T. M., Kyle, J. E., Yaron-Barir, T. M., Binder, Z. A., Li, Y., Strunilin, I., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.06.004 · Cited by 71
A prostate cancer risk element functions as a repressive loop that regulates HOXA13
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InfluentialLabrèche, K., Kinnersley, B., Berzero, G., Stefano, A. L. D., Rahimian, A., Detrait, I., Marie, Y., Grenier‐Boley, B., Hoang‐Xuan, K., Delattre, J., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1825-z · Cited by 70
“Notably, IDH mutant tumours have been shown to reshape 3D chromatin organisation and may reveal new regulatory interactions [14].”
BackgroundEssential role of Cp190 in physical and regulatory boundary formation
Kaushal, A., Dorier, J., Wang, B., Mohana, G., Taschner, M., Cousin, P., Waridel, P., Iseli, C., Semenova, A., Restrepo, S., et al. (2022) · Science Advances · doi:10.1126/sciadv.abl8834 · Cited by 66
“Recombinant protein pull-downs Expression plasmids encoding untagged full-length Cp190[1-1096] and/or Cp60[1-440] (with kanamycin resistance) were cotransformed with a plasmid expressing GFP-tagged CTCF[1-293] (N terminus), CTCF[610-818] (C terminus), Su(Hw)[1-219] (N terminus), Su(Hw)[724-941] (C terminus), Ibf1[1-24…”
BackgroundMethodInfluentialThree-dimensional folding dynamics of the Xenopus tropicalis genome
Niu, L., Shen, W., Shi, Z., Tan, Y., He, N., Wan, J., Sun, J., Zhang, Y., Huang, Y., Wang, W., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00878-z · Cited by 63
HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours
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“Therefore, the resulting loss of insulation between TADs leads to aberrant gene activation, such as the oncogene PDGFRA [189].”
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“A recent study outlined a novel mechanism involved in the pathogenesis of IDH-mutant gliomas: methylation of insulator protein binding sites within DNA, leading to aberrant contact of the PDGFRA promoter with distant enhancer elements, causing overexpression of PDGFRA, a known glioma oncogene (42).”
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Spatial Organization of Chromatin: Emergence of Chromatin Structure During Development
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“For example, depletion of CTCF can drive oncogene activation through nonspecific association between a constitutive enhancer and a promoter for a glioma oncogene normally located in two separate TADs (Flavahan et al. 2016).”
BackgroundDistinct Trends of DNA Methylation Patterning in the Innate and Adaptive Immune Systems
Schuyler, R. P., Merkel, A., Raineri, E., Altucci, L., Vellenga, E., Martens, J. H. A., Pourfarzad, F., Kuijpers, T. W., Burden, F., Farrow, S., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.054 · Cited by 63
“Localized changes in methylation influence nucleosome stability (Jimenez-Schuyler Useche et al., 2013) and affect CTCF binding, altering chromatin topology (Flavahan et al., 2016; Ito et al., 2013).”
The multiple facets of the SMC1A gene
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“In this process, loop domains prevent enhancers from forming incorrect interactions with targets that are placed in a different loop domain (Lupianez et al., 2015; Flavahan et al., 2016).”
BackgroundChowdhary, S., Kainth, A. S., & Gross, D. S. (2017) · Molecular and Cellular Biology · doi:10.1128/mcb.00292-17 · Cited by 61
“When normal chromosome 59 topology is disrupted, developmental malformations or cancer may be the consequence 60 (3-5).”
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Epigenetic and transcriptional mechanisms for the regulation of IL-10
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“Disruptions of CTCF-associated TADs cause rewiring of gene-enhancer interactions and can result in aberrant gene activation that leads to disease[28,29].”
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“This provides potential opportunities for targeting these pathways as therapeutic approaches to IDH mutant cancers, for example, targeting hypermethylation phenotype using epigenetic modulators [63,121,122]; targeting essential metabolic pathways, such as the NAD de novo synthesis pathway [131] or glutaminolysis [29,1…”
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CTCF organizes inter-A compartment interactions through RYBP-dependent phase separation
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“The observed pattern in mutation occurrence suggests that its involvement in tumourgenesis may be linked to prevention of histone demethylation normally required for linage specific differentiation into terminally differentiated progenitors [17,18], in addition to altering the activity of chromosomal topological-regul…”
BackgroundLDB1 establishes multi-enhancer networks to regulate gene expression
Aboreden, N. G., Lam, J. C., Goel, V. Y., Wang, S., Wang, X., Midla, S. C., Quijano, A., Keller, C. A., Giardine, B. M., Hardison, R. C., et al. (2025) · Molecular Cell · doi:10.1016/j.molcel.2024.11.037 · Cited by 61
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Enhancer-gene specificity in development and disease
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Cellular Plasticity and Tumor Microenvironment in Gliomas: The Struggle to Hit a Moving Target
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“Altogeth r, thes studies suggest that IDH1/2 mutations disrupt the chromo omal topology and orche trate a compl te change in the expression profile of the tumor cells, promoti g tumor growth through the induction of oncogenic molecules [42] and the inhibition of pro‐differentiation genes [44].”
BackgroundInfluentialReorganized 3D Genome Structures Support Transcriptional Regulation in Mouse Spermatogenesis
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Higher-Order Chromosomal Structures Mediate Genome Function
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Epigenomics of Major Depressive Disorders and Schizophrenia: Early Life Decides
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“Interestingly, fetal brain meQTLs were strongly enriched in DNA-binding sites for the architectural protein CTCF (Figure 4) that connects higher-order chromatin structure to lineage-specific, but also to aberrant, gene expression [139].”
BackgroundEngineering 3D genome organization
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The multifaceted roles of cohesin in cancer
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“In this process, loop domains prevent enhancers from forming incorrect interactions with targets that are placed in a different loop domain [81, 82].”
BackgroundEpigenetic therapies in acute myeloid leukemia: where to from here?
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Understanding Spatial Genome Organization: Methods and Insights
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“As mentioned briefly above, this was also shown recently by a study demonstrating that IDH mutations promote gliomagenesis by disrupting CTCF binding via hypermethylation, in turn disrupting TAD boundaries and allowing aberrant enhancer–promoter interactions to activate normallyinsulated oncogenes [121].”
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“CTCF-binding sites were also found to be some of the most frequently mutated transcription factor-binding sites in cancers [29,36,37], including HCC [38].”
BackgroundCTCF looping is established during gastrulation in medaka embryosPreprint
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“Such examples have been previously observed in both mammals (9, 11, 67) and Drosophila (10, 68).”
BackgroundOhba, S., Mukherjee, J., Johannessen, T.-C. A., Mancini, A., Chow, T. T., Wood, M. D., Jones, L. E., Mazor, T., Marshall, R. E., Viswanath, P., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-0696 · Cited by 55
“IDH1induced hypermethylation of CCCTC-binding factor–binding sites near the TERT promoter may also contribute to loss of insulation and aberrant TERT promoter activation (47, 48), although postcrisis cells do not exhibit G-CIMP, and the role of methylation in control of TERT promoter activation is controversial (49, 5…”
BackgroundThree-dimensional organization and dynamics of the genome
Szałaj, P., & Plewczyński, D. (2018) · Cell Biology and Toxicology · doi:10.1007/s10565-018-9428-y · Cited by 59
“This allows a constitutive enhancer to interact with a prominent glioma oncogene, the receptor tyrosine kinase gene PDGFRA, located in a neighboring domain (Hnisz et al. 2016; Flavahan et al. 2016).”
BackgroundExploiting metabolic vulnerabilities for personalized therapy in acute myeloid leukemia
Stuani, L., Sabatier, M., & Sarry, J. (2019) · BMC Biology · doi:10.1186/s12915-019-0670-4 · Cited by 66
Crossed wires: 3D genome misfolding in human disease
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“At each level in the chromatin folding hierarchy, the folding patterns exhibit a complex connection to genome function and dysfunction in cellular models of healthy development and disease (Roix et al., 2003; Branco and Pombo, 2006; Fudenberg et al., 2011; Ibn-Salem et al., 2014; Qian et al., 2014; Lupiáñez et al., 20…”
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Chromatin Conformation in Development and Disease
Boltsis, I., Grosveld, F. G., Giraud, G., & Kolovos, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.723859 · Cited by 59
Epigenetic determinants of metastasis
Patel, S. A., & Vanharanta, S. (2016) · Molecular Oncology · doi:10.1016/j.molonc.2016.09.008 · Cited by 58
“Interestingly, DNA methylation in this context can change the affinity of the chromatin insulator protein CTCF to specific target loci, leading to altered chromatin domain structure and activation of oncogenic drivers such as PDGFRA (Flavahan et al., 2016).”
BackgroundSchoenfelder, S., Mifsud, B., Senner, C. E., Todd, C. D., Chrysanthou, S., Darbo, E., Hemberger, M., & Branco, M. R. (2018) · Nature Communications · doi:10.1038/s41467-018-06666-4 · Cited by 54
Masseroli, M., Kaitoua, A., Pinoli, P., & Ceri, S. (2016) · Methods · doi:10.1016/j.ymeth.2016.09.002 · Cited by 56
“- 28 tridimensional structure of the genome [27], mapped to GDM, and investigating, by using public TCGA datasets modeled and made interoperable through GDM, the relationships between the disruption of the boundaries of genomic topologically associating domains (TADs) and various types of cancer, along the direction o…”
MethodThe clinical use of IDH1 and IDH2 mutations in gliomas
Pïcca, A., Berzero, G., Stefano, A. L. D., & Sanson, M. (2018) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2018.1548935 · Cited by 55
“a constitutive enhancer physiologically relegated in a different domain [47].”
BackgroundZNF143 is a regulator of chromatin loop
Wen, Z., Huang, Z.-T., Zhang, R., & Peng, C. (2018) · Cell Biology and Toxicology · doi:10.1007/s10565-018-9443-z · Cited by 41
Mutant IDH in Gliomas: Role in Cancer and Treatment Options
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3D genome and its disorganization in diseases
Li, R., Liu, Y., Hou, Y., Gan, J., Wu, P., & Cheng, L. (2018) · Cell Biology and Toxicology · doi:10.1007/s10565-018-9430-4 · Cited by 56
Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myelomaPreprint
Ciriza, R. O., Kulis, M., Russiñol, N., Chapaprieta, V., Carrasco‐Leon, A., García-Torre, B., Charalampopoulou, S., Clot, G., Beekman, R., Meydan, C., et al. (2020) · Genome Research · doi:10.1101/gr.265520.120 · Cited by 54
Three-dimensional genome organization in immune cell fate and function
Cuartero, S., Stik, G., & Stadhouders, R. (2022) · Nature reviews. Immunology · doi:10.1038/s41577-022-00774-5 · Cited by 56
Integrative analysis revealed potential causal genetic and epigenetic factors for multiple sclerosis
Mo, X., Lei, S., Qian, Q., Guo, Y., Zhang, Y., & Zhang, H. (2019) · Journal of Neurology · doi:10.1007/s00415-019-09476-w · Cited by 55
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“Other mechanisms could include the reconfiguration of chromatin leading to sustained up-regulation of mechanisms activating RAS signaling through PI3K, as has been shown in IDH mutant gliomas [14], with subsequent stimulation of metabolism.”
BackgroundSuper-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer
Tang, S. C., Vijayakumar, U., Zhang, Y., & Fullwood, M. J. (2022) · Cancers · doi:10.3390/cancers14122866 · Cited by 56
Enhancer–promoter specificity in gene transcription: molecular mechanisms and disease associations
Friedman, M. J., Wagner, T., Lee, H., Rosenfeld, M. G., & Oh, S. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01233-y · Cited by 61
Zhong, J., Niu, L., Lin, Z., Bai, X., Chen, Y., Luo, F., Hou, C., & Xiao, C. (2023) · Nature Communications · doi:10.1038/s41467-023-36899-x · Cited by 58
CTCF loss mediates unique DNA hypermethylation landscapes in human cancers
Damaschke, N., Gawdzik, J. C., Avilla, M. N., Yang, B., Svaren, J. P., Roopra, A., Luo, J., Yu, Y. P., Keleş, S., & Jarrard, D. F. (2020) · Clinical Epigenetics · doi:10.1186/s13148-020-00869-7 · Cited by 51
Functional and topographic effects on DNA methylation in IDH1/2 mutant cancers
Bledea, R., Vasudevaraja, V., Patel, S. V., Stafford, J. M., Serrano, J., Esposito, G., Tredwin, L. M., Goodman, N. E., Kloetgen, A., Golfinos, J. G., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-53262-7 · Cited by 52
Therapies for IDH-Mutant Gliomas
Nasany, R. A., & de la Fuente, M. I. (2023) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-023-01265-3 · Cited by 50
“As discussed earlier, IDH mutations lead to a hypermethylation phenotype that results in epigenetic alterations in glioma cells and is possibly linked to gliomagenesis [77, 80].”
BackgroundThe role of insulators and transcription in 3D chromatin organization of fliesPreprint
Chathoth, K. T., Mikheeva, L. A., Crevel, G., Wolfe, J. C., Hunter, I., Beckett-Doyle, S., Cotterill, S., Dai, H., Harrison, A., & Zabet, N. R. (2022) · Genome Research · doi:10.1101/gr.275809.121 · Cited by 46
“Several studies have shown that TAD reorganization leads to changes in transcription that correspond to developmental defects or diseases (Chandra et al. 2015; Lupiáñez et al. 2015; Flavahan et al. 2016; Hnisz et al. 2016; Sun et al. 2018; Kraft et al. 2019).”
The Role of Insulation in Patterning Gene Expression
Özdemir, I., & Gambetta, M. C. (2019) · Genes · doi:10.3390/genes10100767 · Cited by 50
“This model is supported by compelling experimental evidence: (1) Convergently oriented CTCF-bound sites are present at the majority of loop anchors [69,70], (2) deletion of a CTCF site can result in fusion of two adjacent loops [37,66,71,72], (3) loops can be rewired or created by precise inversions or insertions of C…”
BackgroundResultAlteration of genome folding via contact domain boundary insertion
Zhang, D., Huang, P., Sharma, M., Keller, C. A., Giardine, B. M., Zhang, H., Gilgenast, T. G., Phillips‐Cremins, J. E., Hardison, R. C., & Blobel, G. A. (2020) · Nature Genetics · doi:10.1038/s41588-020-0680-8 · Cited by 48
3D genome evolution and reorganization in the Drosophila melanogaster species group
Torosin, N. S., Anand, A., Golla, T. R., Cao, W., & Ellison, C. E. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1009229 · Cited by 46
Deciphering essential cistromes using genome-wide CRISPR screens
Fei, T., Li, W., Peng, J., Xiao, T., Chen, C.-H., Wu, A., Huang, J., Zang, C., Liu, X. S., & Brown, M. A. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1908155116 · Cited by 48
Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements
Zepeda‐Mendoza, C. J., Ibn-Salem, J., Kammin, T., Harris, D. J., Rita, D., Gripp, K. W., MacKenzie, J. J., Gropman, A. L., Graham, B. H., Shaheen, R., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.06.011 · Cited by 48
Oncometabolites in cancer aggressiveness and tumour repopulation
Dando, I., Pozza, E. D., Ambrosini, G., Torrens‐Mas, M., Butera, G., Mullappilly, N., Pacchiana, R., Palmieri, M., & Donadelli, M. (2019) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12513 · Cited by 49
Genome-Wide Association Studies in Glioma
Kinnersley, B., Houlston, R. S., & Bondy, M. L. (2018) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-17-1080 · Cited by 48
“Of vital importance is the use of appropriate model systems to investigate potential tissue- and developmental stage-specific differences in chromatin architecture, from neuronal progenitor cells (130) through to IDH mutated and wild-type tumors (131).”
BackgroundWang, J., Wang, J., Yang, L., Zhao, C., Wu, L.-M. N., Xu, L., Zhang, F., Weng, Q., Wegner, M., & Lu, Q. R. (2020) · Nature Communications · doi:10.1038/s41467-020-17955-2 · Cited by 48
Krichevsky, A. M., & Uhlmann, E. J. (2019) · Neurotherapeutics · doi:10.1007/s13311-018-00702-3 · Cited by 48
Structural variants shape driver combinations and outcomes in pediatric high-grade glioma
Dubois, F. P. B., Shapira, O., Greenwald, N. F., Zack, T. I., Wala, J. A., Tsai, J. W., Crane, A., Baguette, A., Hadjadj, D., Harutyunyan, A. S., et al. (2022) · Nature Cancer · doi:10.1038/s43018-022-00403-z · Cited by 42
Metabolic reprogramming in the pathogenesis of glioma: Update
Masui, K., Onizuka, H., Cavenee, W. K., Mischel, P. S., & Shibata, N. (2019) · Neuropathology · doi:10.1111/neup.12535 · Cited by 48
Making sense of the linear genome, gene function and TADs
Long, H., Greenaway, S., Powell, G., Mallon, A., Lindgren, C. M., & Simon, M. M. (2022) · Epigenetics & Chromatin · doi:10.1186/s13072-022-00436-9 · Cited by 52
Comparative characterization of 3D chromatin organization in triple-negative breast cancers
Kim, T., Han, S., Chun, Y., Yang, H.-J., Min, H., Jeon, S. Y., Kim, J., Moon, H., & Lee, D. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00768-2 · Cited by 49
Epigenetic regulation of neuroblastoma development
Durinck, K., & Speleman, F. (2018) · Cell and Tissue Research · doi:10.1007/s00441-017-2773-y · Cited by 47
The Effect of Molecular Diagnostics on the Treatment of Glioma
Bush, N. A. O., & Butowski, N. A. (2017) · Current Oncology Reports · doi:10.1007/s11912-017-0585-6 · Cited by 47
Rescue of TCA Cycle Dysfunction for Cancer Therapy
Marquez, J. C., Flores, J., Kim, A. H., Nyamaa, B., Nguyen, A. T. T., Park, N., & Han, J. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8122161 · Cited by 47
“The aforementioned CRISPR-mediated disruption of the CTCF binding site caused an upregulation of PDGFRA, a prominent glioma oncogene, and increased cell proliferation [128].”
BackgroundGunn, K., Myllykoski, M., Cao, J. Z., Ahmed, M., Huang, B., Rouaisnel, B., Diplas, B. H., Levitt, M. M., Looper, R., Doench, J. G., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0825 · Cited by 57
Enhancer dysfunction in leukemia
Bhagwat, A. S., Lu, B., & Vakoc, C. R. (2018) · Blood · doi:10.1182/blood-2017-11-737379 · Cited by 45
“Studies in gliomas revealed a distinct mechanism—methylation of the underlying DNA—to restrict CTCF binding and promote enhancer deregulation in cancer [84].”
BackgroundConvergent epigenetic evolution drives relapse in acute myeloid leukemia
Nuno, K. A., Azizi, A., Köhnke, T., Lareau, C. A., Ediriwickrema, A., Corces, M. R., Satpathy, A. T., & Majeti, R. (2024) · eLife · doi:10.7554/elife.93019 · Cited by 50
“Recent studies profiling the chromatin landscape of certain cancers indicate that the fine regulation of chromatin activity is critical for tumor suppression ( Hnisz et al., 2016 ; Flavahan et al., 2016 ).”
The proto CpG island methylator phenotype of sessile serrated adenomas/polyps
Parker, H. R., Orjuela, S., Oliveira, A. M., Cereatti, F., Sauter, M. M., Heinrich, H. S., Tanzi, G., Weber, A., Komminoth, P., Vavricka, S. R., et al. (2018) · Epigenetics · doi:10.1080/15592294.2018.1543504 · Cited by 44
Disruption of the 3D Cancer Genome Blueprint
Achinger-Kawecka, J., & Clark, S. J. (2016) · Epigenomics · doi:10.2217/epi-2016-0111 · Cited by 45
Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes
Ringel, A. R., Szabo, Q., Chiariello, A. M., Chudzik, K., Schöpflin, R., Rothe, P., Mattei, A. L., Zehnder, T., Harnett, D., Laupert, V., et al. (2022) · Cell · doi:10.1016/j.cell.2022.09.006 · Cited by 50
“counterparts, were more frequently coexpressed when located within the same TAD, similar to past reports (Figure 6C; Flavahan et al., 2016; Nora et al., 2012; Shen et al., 2012; Zhan et al., 2017).”
ResultEpigenetics of Most Aggressive Solid Tumors: Pathways, Targets and Treatments
Martínez‐Useros, J., Martin-Galan, M., Florez-Cespedes, M., & García‐Foncillas, J. (2021) · Cancers · doi:10.3390/cancers13133209 · Cited by 46
Mechanisms of sex determination and X-chromosome dosage compensation
Meyer, B. J. (2022) · Genetics · doi:10.1093/genetics/iyab197 · Cited by 39
Gudla, P. R., Nakayama, K., Pegoraro, G., & Misteli, T. (2017) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2017.82.033761 · Cited by 47
“Alterations in genome folding and organization have been linked to cancer (Flavahan et al. 2016) and developmental syndromes (Lupiáñez et al. 2015; Franke et al. 2016), highlighting the importance of 3D genome architecture in physiological and diseased states.”
BackgroundOverview of DNA methylation in adult diffuse gliomas
Aoki, K., & Natsume, A. (2019) · Brain Tumor Pathology · doi:10.1007/s10014-019-00339-w · Cited by 45
Shareef, S. J., Bevill, S. M., Raman, A. T., Aryee, M. J., van Galen, P., Hovestadt, V., & Bernstein, B. (2021) · Nature Biotechnology · doi:10.1038/s41587-021-00910-x · Cited by 43
Self-citationThe role of 3D genome organization in disease: From compartments to single nucleotides
Chakraborty, A., & Ay, F. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.07.005 · Cited by 39
LncRNA FOXD1‐AS1 acts as a potential oncogenic biomarker in glioma
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Park, Y. J., Lee, S., Lim, S., Nahmgoong, H., Ji, Y., Huh, J. Y., Alfadda, A. A., Kim, S., & Kim, J. B. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2021073118 · Cited by 44
“These changes in CTCF occupancy have been linked to pathogenicity by causing aberrant chromosome looping between distal cis-regulatory elements and their target promoters that promote altered gene expression (10, 12, 13).”
BackgroundGliomas Genomics and Epigenomics: Arriving at the Start and Knowing It for the First Time
Filbin, M. G., & Suvà, M. L. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044208 · Cited by 46
“This can lead to an aberrant interaction between constitutive enhancers and oncogenes such as PDGFRA, thus contributing to transformation (98).”
Self-citationPrognostic value of a microRNA signature as a novel biomarker in patients with lower-grade gliomas
Qian, Z., Li, Y., Fan, X., Zhang, C., Wang, Y., Jiang, T., & Liu, X. (2017) · Journal of Neuro-Oncology · doi:10.1007/s11060-017-2704-5 · Cited by 43
“IDH mutations and the 1p/19q co-deletion are particularly notable molecular alterations that occur in the very early stage of gliomagenesis and are considered key prognostic factors for patients with LGGs according to a new WHO classification [1, 17, 27].”
BackgroundLee, M. H., Kim, J., Kim, S., et al. (2019) · World Neurosurgery · doi:10.1016/j.wneu.2019.01.157 · Cited by 43
Cohesin Mutations in Cancer: Emerging Therapeutic Targets
Antony, J., Chin, C. V., & Horsfield, J. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136788 · Cited by 43
Metadata
- Authors
- Flavahan, W. A., Drier, Y., Liau, B. B., Gillespie, S. M., Venteicher, A. S., Stemmer-Rachamimov, A. O., Suvà, M. L., & Bernstein, B. E.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Corresponding author
- Bernstein, Bradley E.
- ORCID
- Venue
- Nature
- Published
- 2015-12-23
- Volume
- 529
- Issue
- 7584
- Pages
- 110-114
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4831574
- OpenAlex
- W2222531233
- Semantic Scholar
- 749f7a7a14c60dad4fd2f91895fe8ba804d72f81
- Cited by
- 1,288
- References
- 44
- Citations by year
- 2026: 71 · 2025: 81 · 2024: 106 · 2023: 119 · 2022: 142 · 2021: 144 · 2020: 139 · 2019: 147 · 2018: 110 · 2017: 135 · 2016: 89 · 2015: 1
- FWCI
- 62.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Human Genome Research Institute (U54HG006991)
- National Cancer Institute (DP1CA216873, P50CA165962)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- IDH-mutant glioma, CTCF, PDGFRA, chromatin topology, topologically associating domains, DNA methylation, 2-hydroxyglutarate, TET enzymes, G-CIMP, enhancer-promoter interactions, hypomethylating agents, gliomagenesis
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Base Sequence, Binding Sites, Cell Transformation, Neoplastic, Cells, Cultured, Chromatin, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Glioma, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, Oncogenes, Phenotype, Protein Binding, Repressor Proteins, Down-Regulation, Up-Regulation, Gene Expression Regulation, Neoplastic, Cell Cycle Proteins, CpG Islands, DNA Methylation, Receptor, Platelet-Derived Growth Factor alpha, Insulator Elements, Epigenesis, Genetic, Cell Proliferation, CRISPR-Cas Systems
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