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Transcription factors as readers and effectors of DNA methylation
Open accessAbstract
Recent technological advances have made it possible to decode DNA methylomes at single-base-pair resolution under various physiological conditions. Many aberrant or differentially methylated sites have been discovered, but the mechanisms by which changes in DNA methylation lead to observed phenotypes, such as cancer, remain elusive. The classical view of methylation-mediated protein–DNA interactions is that only proteins with a methyl-CpG binding domain (MBD) can interact with methylated DNA. However, evidence is emerging to suggest that transcription factors lacking a MBD can also interact with methylated DNA. The identification of these proteins and the elucidation of their characteristics and the biological consequences of methylation-dependent transcription factor–DNA interactions are important stepping stones towards a mechanistic understanding of methylation-mediated biological processes, which have crucial implications for human development and disease.
Overview
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Written from the paper’s full text.
TL;DR
This review/analysis argues that transcription factors lacking methyl-CpG binding domains can act as sequence-specific readers and effectors of methylated DNA, extending the classical MBD-only model. It combines in vitro discovery screens with in vivo ENCODE-based integration to show that many TF binding sites overlap highly methylated CpGs, while stressing unresolved causality and physiological relevance.
Key findings
- Classical MBD proteins bind methylated DNA without strong sequence specificity, but emerging evidence shows TFs such as Kaiso, CEBPα, ZFP57/KAP1, KLF4 and others can recognize methylated motifs in a sequence-dependent manner.
- A protein microarray probing 1,321 human TFs and 210 cofactors with 154 methylated motifs found that 150 motifs bound at least one protein; 41 TFs and 6 cofactors bound at least one methylated sequence, with binding spread across families such as zf-C2H2, homeobox, bHLH, forkhead, bZIP and HMG.
- An MS/MS pulldown from mouse ES nuclear extracts identified 19 proteins preferring methylated over unmethylated probes, including known MBD proteins and TFs; a distinct set was found in neuronal progenitor cells.
- In H1 human ES cells, 77,124 of 258,188 DNase I hypersensitive sites (29.9%) had average CpG methylation above 80%; for CEBPβ, 6,675 of 15,557 ChIP–seq peaks (42.9%) exceeded 80% methylation, and motif analysis found 3,894 of 15,557 CEBPβ sites (25.0%) carried a highly methylated CpG in the enriched motif, compared with 7.7% for E2F6, 5.2% for RFX5, 3.0% for KLF4 and 1.6% for BACH1.
Methods
- This is a review/Analysis article synthesizing literature on DNA methylation readers and effectors, focused mainly on mammalian methylated CpG sites.
- It describes high-throughput discovery approaches including tandem mass spectrometry pulldown, functional protein microarrays, DNA microarrays and ChIP–BS-seq.
- It also reports an integrative in vivo analysis: ENCODE H1 hESC DNase I hypersensitivity peaks and whole-genome bisulfite methylome data were overlaid; TF ChIP–seq peaks were called with IDR and compared with methylation levels; MEME was used for motif discovery, with NRF1 and TAF1 as negative controls.
Limitations
- The authors state that causality between DNA methylation and TF binding remains unclear, that a more comprehensive catalogue of readers/effectors is needed, and that in vivo validation and physiological relevance are still major challenges; many interactions rest mainly on in vitro evidence.
- Method-specific limitations stated include: MS/MS probes are often generic, so sequence specificity is elusive; DNA microarrays require prior knowledge of a candidate TF; ChIP–BS-seq requires prior knowledge and suitable antibodies; and Kaiso in vivo results conflict across cell types, suggesting cell-type specificity.
- Evident from the text: the in vivo integration is constrained by limited available ChIP–seq data (only six TFs in H1 cells) and uses a stringent >80% methylation cutoff, making the reported overlap estimates conservative; as a review, it does not present a single new experimental cohort.
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Claims the paper makes
100 Not checked yet · 21 Own interpretation · 10 Own result · 6 Own method · 1 No basis given
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
“of the 15,557 ChIP–seq peaks identified for CEBPβ, 6,675 (42.9%) had a methylation level greater than 80%.”
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Overall, 77,124 (29.9%) of the 258,188 DHSs detected in H1 cells had an average methylation level greater than 80% at CpG sites (FIG. 2a)”
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
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In the paper
“Based on the analysis of KLF4 binding in ES cells, we also found that KLF4 binds to methylated enhancer regions53”
§ Transcription factors as readers and effectors of DNA methylation > Features of methylated-DNA–protein interaction > Cis-regulatory elements
What the sources say
- Not checked yetcites [53] Hu, S. et al. DNA methylation presents distinct binding sites for human transcription factors. eLife 2, e00726 (2013). This study identifies the transcription factors that preferentially bind to methylated DNA using a protein microarray-based approach and verified that endogenous KLF4 binds to methylated DNA in human ES cells. source
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In the paper
“A motif could be reconstructed with these 3,894 binding peaks, which represented the methylated motif for CEBPβ (FIG. 2c).”
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
hedgedcorrelational- 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
“Among the 6,675 peaks with a high methylation level, 3,894 carried a highly methylated (>80%) CpG site within the enriched motifs.”
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“indicating that a substantial fraction of their binding sites are located in highly methylated regions (FIG. 2a).”
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The most significantly enriched motif did not contain a CpG site.”
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The DNA methylation levels within the ChIP–seq peaks showed a bimodal distribution for all TFs except RXRα”
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“when the same analysis was applied to those peaks that have high methylation levels, a significantly enriched motif containing a CpG site at position 4 was discovered (FIG. 2b).”
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Indeed, we observed a large overlap between known pioneer TFs and proteins that bind to methylated DNA (for example, forkhead box protein A (FOXA) and GATA families, which are the best-studied pioneer factors)106,108–110.”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Pioneer TFs
What the sources say
- Not checked yetcites [106] Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011). source
- Not checked yetcites [108] Bossard, P. & Zaret, K. S. GATA transcription factors as potentiators of gut endoderm differentiation. Development 125, 4909–4917 (1998). source
- Not checked yetcites [109] Laverriere, A. C. et al. GATA-4/5/6, a subfamily of three transcription factors transcribed in developing heart and gut. J. Biol. Chem. 269, 23177–23184 (1994). source
- Not checked yetcites [110] Liu, J. K., DiPersio, C. M. & Zaret, K. S. Extracellular signals that regulate liver transcription factors during hepatic differentiation in vitro. Mol. Cell. Biol. 11, 773–784 (1991). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 38
- Probably not a substantial claim. 7
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In the paper
“neither NRF1 (FIG. 2a) nor TAF1 (Supplementary information S1 (figure)) showed a bimodal distribution, demonstrating that these TFs only bind to regions with low levels of methylation.”
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: NRF1 and TAF1 do not interact with methylated DNA.
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
“25.0% (3,894 out of 15,557), 7.7% (1,103 out of 14,396), 5.2% (88 out of 1,695), 3.0% (115 out of 3,793) and 1.6% (186 out of 11,457) of binding sites were highly methylated for CEBPβ, E2F6, RFX5, KLF4 and BACH1, respectively (FIG. 2c).”
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“a bZIP herpesvirus protein, Zta, was found to bind to methylated regulatory elements and control the epigenetic landscape during the latency-to-lytic phase transition in infected mammalian cells45”
§ Transcription factors as readers and effectors of DNA methylation > Readers of methylated DNA
What the sources say
- Not checked yetcites [45] Karlsson, Q. H., Schelcher, C., Verrall, E., Petosa, C. & Sinclair, A. J. Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. PLoS Pathog. 4, e1000005 (2008). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the basic leucine zipper (bZIP) CCAAT/enhancer-binding protein-α (CEBPα)42, the zinc-finger protein ZFP57 and its cofactor KRAB-associated protein 1 (KAP1; also known as TIF1β)43,44 were shown to interact with specific methylated sequences.”
§ Transcription factors as readers and effectors of DNA methylation > Readers of methylated DNA
What the sources say
- Not checked yetcites [42] Rishi, V. et al. CpG methylation of half-CRE sequences creates C/EBPα binding sites that activate some tissue-specific genes. Proc. Natl Acad. Sci. USA 107, 20311–20316 (2010). source
- Not checked yetcites [43] Quenneville, S. et al. In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions. Mol. Cell 44, 361–372 (2011). This paper demonstrates that ZFP57 and its cofactor KAP1 affect chromatin by interacting with methylated ICRs in embryonic stem cells. source
- Not checked yetcites [44] Liu, Y., Toh, H., Sasaki, H., Zhang, X. & Cheng, X. An atomic model of Zfp57 recognition of CpG methylation within a specific DNA sequence. Genes Dev. 26, 2374–2379 (2012). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The authors applied the same approach to neuronal progenitor cells and found that a large and distinct set of proteins showed preferential binding to mCpG sites, suggesting that the interaction with mCpG is dynamic and thus varies under different physiological conditions.”
§ Transcription factors as readers and effectors of DNA methylation > High-throughput reader discovery > Tandem mass spectrometry
What the sources say
- Not checked yetcites [51] Spruijt, C. G. et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152, 1146–1159 (2013). This paper describes the identification of proteins that interact with mCpG sites, 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) in ES cells and neuronal progenitor cells using a MS/MS-based approach. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“the reduction of DNA methylation led to a decrease in H3K27ac marks, suggesting an active role of DNA methylation in regulating enhancer activity.”
§ Transcription factors as readers and effectors of DNA methylation > Features of methylated-DNA–protein interaction > Cis-regulatory elements
What the sources say
- Not checked yetcites [79] Charlet, J. et al. Bivalent regions of cytosine methylation and H3K27 acetylation suggest an active role for DNA methylation at enhancers. Mol. Cell 62, 422–431 (2016). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“CEBPα is known to bind a particular sequence element, 5′-TGACGTCA42. However, when the CpG is methylated, CEBPα can effectively recognize half of the motif: 5′-mCGTCA42.”
§ Transcription factors as readers and effectors of DNA methylation > Features of methylated-DNA–protein interaction > Sequence specificity
What the sources say
- Not checked yetcites [42] Rishi, V. et al. CpG methylation of half-CRE sequences creates C/EBPα binding sites that activate some tissue-specific genes. Proc. Natl Acad. Sci. USA 107, 20311–20316 (2010). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the recent crystal structure of mouse ZFP57 in complex with a methylated DNA sequence demonstrated that its two zinc-fingers interact with methylated DNA, and that an arginine (Arg178), which is involved in hydrophobic interactions, plays a crucial part in mCpG binding44.”
§ Transcription factors as readers and effectors of DNA methylation > Features of methylated-DNA–protein interaction > Protein domains that interact with methylated DNA
What the sources say
- Not checked yetcites [44] Liu, Y., Toh, H., Sasaki, H., Zhang, X. & Cheng, X. An atomic model of Zfp57 recognition of CpG methylation within a specific DNA sequence. Genes Dev. 26, 2374–2379 (2012). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“approximately 6.7% of the mouse genome is differentially methylated, mostly at distal cis-regulatory regions77.”
§ Transcription factors as readers and effectors of DNA methylation > Features of methylated-DNA–protein interaction > Cis-regulatory elements
What the sources say
- Not checked yetcites [77] Hon, G. C. et al. Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues. Nat. Genet. 45, 1198–1206 (2013). source
plainn = 17- Asserted: passes — The authors put it forward as true.
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In the paper
“the DNA probes used in this approach are typically generic and, therefore, sequence specificity of observed interactions remains elusive.”
§ Transcription factors as readers and effectors of DNA methylation > High-throughput reader discovery > Tandem mass spectrometry
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“prior knowledge of a candidate TF is required because it can be cumbersome to survey an entire TF family.”
§ Transcription factors as readers and effectors of DNA methylation > High-throughput reader discovery > DNA microarray
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Most of these factors were found to bind to only a few methylated sequences, suggesting that the interactions are not only methylation-dependent but also sequence-specific.”
§ Transcription factors as readers and effectors of DNA methylation > High-throughput reader discovery > Functional protein microarray
What the sources say
- Not checked yetcites [53] Hu, S. et al. DNA methylation presents distinct binding sites for human transcription factors. eLife 2, e00726 (2013). This study identifies the transcription factors that preferentially bind to methylated DNA using a protein microarray-based approach and verified that endogenous KLF4 binds to methylated DNA in human ES cells. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“A subsequent validation assay showed that some of these TFs indeed bind to methylated DNA in vivo and regulate gene expression53.”
§ Transcription factors as readers and effectors of DNA methylation > High-throughput reader discovery > Functional protein microarray
What the sources say
- Not checked yetcites [53] Hu, S. et al. DNA methylation presents distinct binding sites for human transcription factors. eLife 2, e00726 (2013). This study identifies the transcription factors that preferentially bind to methylated DNA using a protein microarray-based approach and verified that endogenous KLF4 binds to methylated DNA in human ES cells. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A separate study suggested that an arginine and glutamate pair in KLF4 recognizes the mCpG site68.”
§ Transcription factors as readers and effectors of DNA methylation > Features of methylated-DNA–protein interaction > Protein domains that interact with methylated DNA
What the sources say
- Not checked yetcites [68] Liu, Y. et al. Structural basis for Klf4 recognition of methylated DNA. Nucleic Acids Res. 42, 4859–4867 (2014). This study determined the crystal structure of the KLF4-methylated DNA complex and provided the structural basis for mCpG–TF interactions. source
hedgeddirect- 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
“although KLF4 recognizes a non-methylated canonical motif of 5′-TTTACGCC, it has been demonstrated that KLF4 specifically recognizes a 5′-TCCmCGCCC motif only when the CpG is methylated53.”
§ Transcription factors as readers and effectors of DNA methylation > Features of methylated-DNA–protein interaction > Sequence specificity
What the sources say
- Not checked yetcites [53] Hu, S. et al. DNA methylation presents distinct binding sites for human transcription factors. eLife 2, e00726 (2013). This study identifies the transcription factors that preferentially bind to methylated DNA using a protein microarray-based approach and verified that endogenous KLF4 binds to methylated DNA in human ES cells. source
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
“it requires prior knowledge of mCpG-binding proteins and the availability of antibodies that are directed against the proteins of interest.”
§ Transcription factors as readers and effectors of DNA methylation > High-throughput reader discovery > ChIP–BS-seq
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“when the paternal ICR is methylated, CTCF cannot bind to the ICR, thus allowing the activation of downstream genes by distal enhancers.”
§ Transcription factors as readers and effectors of DNA methylation > Cause or consequence? > Protein binding affects the DNA methylation status
What the sources say
- Not checked yetcites [81] Bell, A. C. & Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482–485 (2000). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These methylation regions are overrepresented in DHSs and are evolutionarily conserved”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Activation or repression
What the sources say
- Not checked yetcites [101] Wan, J. et al. Characterization of tissue-specific differential DNA methylation suggests distinct modes of positive and negative gene expression regulation. BMC Genomics 16, 49 (2015). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Insertion of the binding site induced CTCF binding and resulted in a reduced methylation level in local genomic regions.”
§ Transcription factors as readers and effectors of DNA methylation > Cause or consequence? > Protein binding affects the DNA methylation status
What the sources say
- Not checked yetcites [78] Stadler, M. B. et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480, 490–495 (2011). This paper demonstrates that some proteins, such as CTCF and REST, can reduce DNA methylation levels at the genomic regions near their binding regions. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Methylation in promoters is often considered the hallmark for gene repression99.”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Activation or repression
What the sources say
- Not checked yetcites [99] Baylin, S. B. DNA methylation and gene silencing in cancer. Nat. Clin. Pract. Oncol. 2, S4–S11 (2005). source
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.
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
“Yet, binding to an mCpG site is just one approach for a pioneer TF to access condensed chromatin. Other pioneer TFs might have alternative approaches such as binding to partial motifs.”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Pioneer TFs
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. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“Although only approximately 25% of known TF binding motifs contain at least one CpG site98, through such indirect crosstalk mechanisms, the binding of TFs without CpGs in their binding motifs could also be influenced by DNA methylation.”
§ Transcription factors as readers and effectors of DNA methylation > Cause or consequence? > DNA methylation dictates protein–DNA interactions
What the sources say
- Not checked yetcites [98] Blattler, A. & Farnham, P. J. Cross-talk between site-specific transcription factors and DNA methylation states. J. Biol. Chem. 288, 34287–34294 (2013). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“One is heterochromatin (or condensed chromatin), in which DNA sequences and histones are highly condensed, and genes in these regions are inactive. The other form is euchromatin (or open chromatin), in which DNA sequences are largely accessible to TFs, and genes in these regions can be activated102,103.”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Pioneer TFs
What the sources say
- Not checked yetcites [102] Kornberg, R. D. Chromatin structure: a repeating unit of histones and DNA. Science 184, 868–871 (1974). source
- Not checked yetcites [103] Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007). source
plain- 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. It may state two separate claims as one.
In the paper
“These binding sites often correlated with novel DHSs in the TKO cells, which exhibited predominantly low methylation levels due to their generation in cells lacking DNMTs.”
§ Transcription factors as readers and effectors of DNA methylation > Cause or consequence? > DNA methylation dictates protein–DNA interactions
What the sources say
- Not checked yetcites [97] Domcke, S. et al. Competition between DNA methylation and transcription factors determines binding of NRF1. Nature 528, 575–579 (2015). This paper shows that the removal of DNA methylation would create novel binding sites for NRF1 and thus affect the NRF1–DNA interactions in vivo , whereas other studies showed that DNA methylation could affect TF–DNA interactions in vitro. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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.
In the paper
“Deletion of CTCF motifs within the construct led to hypermethylation and thus decreased NRF1 binding, suggesting that NRF1 binding in vivo depends on both methylation levels and co-occurring TFs, such as CTCF97.”
§ Transcription factors as readers and effectors of DNA methylation > Cause or consequence? > DNA methylation dictates protein–DNA interactions
What the sources say
- Not checked yetcites [97] Domcke, S. et al. Competition between DNA methylation and transcription factors determines binding of NRF1. Nature 528, 575–579 (2015). This paper shows that the removal of DNA methylation would create novel binding sites for NRF1 and thus affect the NRF1–DNA interactions in vivo , whereas other studies showed that DNA methylation could affect TF–DNA interactions in vitro. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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.
In the paper
“novel NRF1 binding sites were hypermethylated in the wild-type cell line97, suggesting that the removal of DNA methylation in TKO cells generated new binding sites for NRF1.”
§ Transcription factors as readers and effectors of DNA methylation > Cause or consequence? > DNA methylation dictates protein–DNA interactions
What the sources say
- Not checked yetcites [97] Domcke, S. et al. Competition between DNA methylation and transcription factors determines binding of NRF1. Nature 528, 575–579 (2015). This paper shows that the removal of DNA methylation would create novel binding sites for NRF1 and thus affect the NRF1–DNA interactions in vivo , whereas other studies showed that DNA methylation could affect TF–DNA interactions in vitro. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“although CTCF is known to change the local methylation status78, it has been shown that the binding of CTCF is also methylation sensitive96.”
§ Transcription factors as readers and effectors of DNA methylation > Cause or consequence? > DNA methylation dictates protein–DNA interactions
What the sources say
- Not checked yetcites [78] Stadler, M. B. et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480, 490–495 (2011). This paper demonstrates that some proteins, such as CTCF and REST, can reduce DNA methylation levels at the genomic regions near their binding regions. source
- Not checked yetcites [96] Maurano, M. T. et al. Role of DNA methylation in modulating transcription factor occupancy. Cell Rep. 12, 1184–1195 (2015). source
boosteddirect- 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.
In the paper
“In one study, the authors observed that the binding of CTCF in an exon region created a roadblock for RNA polymerase II elongation and thus promoted the inclusion of the exon112.”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Splicing regulation
What the sources say
- Not checked yetcites [112] Shukla, S. et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479, 74–79 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“The mCpG-binding protein KLF4 was also shown to be a pioneer factor105,111.”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Pioneer TFs
What the sources say
- Not checked yetcites [105] Iwafuchi-Doi, M. & Zaret, K. S. Pioneer transcription factors in cell reprogramming. Genes Dev. 28, 2679–2692 (2014). source
- Not checked yetcites [111] Buganim, Y., Faddah, D. A. & Jaenisch, R. Mechanisms and models of somatic cell reprogramming. Nat. Rev. Genet. 14, 427–439 (2013). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Pioneer TFs are a unique subset of TFs that drive these chromatin changes.”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Pioneer TFs
What the sources say
- Not checked yetcites [105] Iwafuchi-Doi, M. & Zaret, K. S. Pioneer transcription factors in cell reprogramming. Genes Dev. 28, 2679–2692 (2014). source
- Not checked yetcites [106] Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011). source
plaindirect- 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.
In the paper
“Chromatin organization is dynamic, and the different types of chromatin can change from one form to another during development or differentiation104”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Pioneer TFs
What the sources say
- Not checked yetcites [104] Ho, L. & Crabtree, G. R. Chromatin remodelling during development. Nature 463, 474–484 (2010). source
plain- 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.
In the paper
“Sato et al.86 demonstrated that DNMT3A and DNMT3B interact with an orphan nuclear receptor, NR6A1 (nuclear receptor subfamily 6 group A member 1), and that this interaction induced the methylation of the OCT4 (also known as OCT3 and POU5F1) promoter carrying the NR6A1 binding site.”
§ Transcription factors as readers and effectors of DNA methylation > Cause or consequence? > Protein binding affects the DNA methylation status
What the sources say
- Not checked yetcites [86] Sato, N., Kondo, M. & Arai, K. The orphan nuclear receptor GCNF recruits DNA methyltransferase for Oct-3/4 silencing. Biochem. Biophys. Res. Commun. 344, 845–851 (2006). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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
“Differences in chromatin states will either create or eliminate TF binding sites and thus lead to differential TF binding.”
§ Transcription factors as readers and effectors of DNA methylation > Cause or consequence? > DNA methylation dictates protein–DNA interactions
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“A typical characteristic of pioneer TFs is their ability to bind directly to heterochromatic DNA and recruit other factors to change the status to euchromatin to initiate transcription105,106.”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Pioneer TFs
What the sources say
- Not checked yetcites [105] Iwafuchi-Doi, M. & Zaret, K. S. Pioneer transcription factors in cell reprogramming. Genes Dev. 28, 2679–2692 (2014). source
- Not checked yetcites [106] Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011). source
plaindirect- 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.
In the paper
“Although CTCF motifs were significantly enriched in differentially methylated regions associated with alternative splicing, other motifs were also enriched”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Splicing regulation
What the sources say
- Not checked yetcites [115] Wan, J. et al. Integrative analysis of tissue-specific methylation and alternative splicing identifies conserved transcription factor binding motifs. Nucleic Acids Res. 41, 8503–8514 (2013). source
plaincorrelational- 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.
In the paper
“IDH mutant gliomas have been shown to exhibit hypermethylation at CTCF binding sites, which leads to a reduction in CTCF binding”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Human diseases
What the sources say
- Not checked yetcites [117] Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature (2015). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Many studies have shown that aberrant DNA methylation is associated with various human diseases, including some types of cancer19–21.”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Human diseases
What the sources say
- Not checked yetcites [19] Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415–428 (2002). source
- Not checked yetcites [20] Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683–692 (2007). source
- Not checked yetcites [21] Jones, P. A. & Laird, P. W. Cancer epigenetics comes of age. Nat. Genet. 21, 163–167 (1999). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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.
In the paper
“A comparison of methylation levels between queen and worker bees revealed that intron-containing histone genes were highly methylated, whereas intronless histone genes were not methylated”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Splicing regulation
What the sources say
- Not checked yetcites [114] Lyko, F. et al. The honey bee epigenomes: differential methylation of brain DNA in queens and workers. PLoS Biol. 8, e1000506 (2010). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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.
In the paper
“loss of CTCF in topologically associated domains removed the domain boundary and caused aberrant gene activation117.”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Human diseases
What the sources say
- Not checked yetcites [117] Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“The IDH genes (IDH1 and IDH2) encode isocitrate dehydrogenases, and mutations in these genes are among the most frequent found in diffuse gliomas118,119.”
§ Transcription factors as readers and effectors of DNA methylation > Biological consequences > Human diseases
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- 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
“Of note, this new concept does not refute the conventional view that most TFs do not interact with methylated DNA.”
§ Transcription factors as readers and effectors of DNA methylation > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Rests on an assumption: Most transcription factors do not interact with methylated DNA.
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
“Here, we have focused on this exciting and novel concept with a full awareness that it may apply only to a subset of TFs and to a subset of their binding sites.”
§ Transcription factors as readers and effectors of DNA methylation > Conclusions
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
The paper relies on this without support.
NRF1 and TAF1 do not interact with methylated DNA.
“we selected two TFs (nuclear respiratory factor 1 (NRF1) and transcription initiation factor TFIID subunit 1 (TAF1)), which are known not to interact with methylated DNA (based on our current knowledge), as negative controls”
The paper relies on this without support.
DNA in heterochromatin is often methylated and tightly wrapped around nucleosomes, making it inaccessible to most transcription factors.
“As DNA in heterochromatin is wrapped tightly around the nucleosomes and is often methylated, it is inaccessible to most TFs; pioneer TFs must possess special features to enable protein–DNA interactions.”
The paper relies on this without support.
Splicing occurs co-transcriptionally.
“However, it is now well-established that splicing occurs co-transcriptionally, which means that DNA modification could influence RNA splicing.”
The paper relies on this without support.
The role of MBD proteins as non-sequence-specific methylation readers has been fairly well studied.
“Although the role of MBD proteins, as non-sequence-specific methylation readers, has been fairly well-studied, the biological functions of an emerging class of sequence-specific methylation readers and/or effectors remain elusive.”
The paper relies on this without support.
The biological functions of sequence-specific methylation readers and/or effectors remain elusive.
“Although the role of MBD proteins, as non-sequence-specific methylation readers, has been fairly well-studied, the biological functions of an emerging class of sequence-specific methylation readers and/or effectors remain elusive.”
The paper relies on this without support.
Methylation readers typically bind both methylated and unmethylated sites.
“A methylation reader usually interacts with both methylated sites and unmethylated sites.”
The paper relies on this without support.
Most transcription factors do not interact with methylated DNA.
“Of note, this new concept does not refute the conventional view that most TFs do not interact with methylated DNA.”
The paper relies on this without support.
The mechanism by which altered epigenetic state causes disease remains elusive.
“However, the mechanism by which the altered epigenetic state causes disease remains elusive.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition, acetylation of lysine 27 of histone 3 (H3K27ac) is associated with the active state of both elements.”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [13]
Experimental — accuracy not yet measuredIn the citing paper
“In addition, studies suggest that numerous transcription factors (TFs) can also directly sense the state of cytosine methylation through the modulation of their binding affinity and specificity (26).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [26]
In the citing paper
“The development of high-throughput assays for TF-DNA interaction has identified many transcription factors with binding specificity altered by the presence of 5mC in recognition sequences (26).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [26]
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
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
“For example, the studies showing that Kaiso binds to methylated DNA in vivo58–60 were focused on a few genes or genomic regions rather than genome-wide surveys.”
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
“Similarly, Kaiso was shown to bind to the methylated promoter of the MTA2 gene in HeLa cells61. Another study, which used a quantitative ChIP–PCR assay, demonstrated that Kaiso binds to the methylated promoters of CDKN2A, MGMT and HIC1 in both HCT116 and Colo320 human colon cancer cell lines62.”
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
§ Transcription factors as readers and effectors of DNA methylation > Methylated DNA–TF interactions in vivo
“uniform peaks were called using the Irreproducible Discovery Rate (IDR) method66.”
§ Transcription factors as readers and effectors of DNA methylation > References
“66. Li JJ Jiang CR Brown JB Huang H Bickel PJ Sparse linear modeling of next-generation mRNA sequencing (RNA-Seq) data for isoform discovery and abundance estimation Proc. Natl Acad. Sci. USA 108 19867 19872 2011”
Citations
Cites
MEME SUITE: tools for motif discovery and searching
Bailey, T. L., Boden, M., Buske, F. A., Frith, M., Grant, C. E., Clementi, L., Ren, J., Li, W. W., & Noble, W. S. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp335 · Cited by 10,648
Jaenisch, R., & Bird, A. (2003) · Nature Genetics · doi:10.1038/ng1089 · Cited by 6,325
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
IDH1 and IDH2 Mutations in Gliomas
Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808710 · Cited by 5,847
Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1
Tahiliani, M., Koh, K. P., Shen, Y., Pastor, W. A., Bandukwala, H., Brudno, Y., Agarwal, S., Iyer, L. M., Liu, D. R., Aravind, L., et al. (2009) · Science · doi:10.1126/science.1170116 · Cited by 5,836
The fundamental role of epigenetic events in cancer
Jones, P. A., & Baylin, S. B. (2002) · Nature Reviews Genetics · doi:10.1038/nrg816 · Cited by 5,648
Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2
Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., & Zoghbi, H. Y. (1999) · Nature Genetics · doi:10.1038/13810 · Cited by 4,990
Human DNA methylomes at base resolution show widespread epigenomic differences
Lister, R., Pelizzola, M., Dowen, R. H., Hawkins, R. D., Hon, G., Tonti-Filippini, J., Nery, J. R., Lee, L., Ye, Z., Ngo, Q.-M., et al. (2009) · Nature · doi:10.1038/nature08514 · Cited by 4,673
Jones, P. A., & Baylin, S. B. (2007) · Cell · doi:10.1016/j.cell.2007.01.029 · Cited by 4,515
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154
Genome-wide maps of chromatin state in pluripotent and lineage-committed cells
Mikkelsen, T. S., Ku, M., Jaffe, D. B., Issac, B., Lieberman, E., Giannoukos, G., Alvarez, P., Brockman, W., Kim, T.-K., Koche, R. P., et al. (2007) · Nature · doi:10.1038/nature06008 · Cited by 4,129
Establishing, maintaining and modifying DNA methylation patterns in plants and animals
Law, J. A., & Jacobsen, S. E. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2719 · Cited by 3,925
Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., He, C., & Zhang, Y. (2011) · Science · doi:10.1126/science.1210597 · Cited by 3,451
DNA methylation landscapes: Provocative insights from epigenomics
Suzuki, M. M., & Bird, A. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2341 · Cited by 3,039
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875
DNA methylation and human disease
Robertson, K. D. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1655 · Cited by 2,864
Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA
He, Y., Li, B.-Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., et al. (2011) · Science · doi:10.1126/science.1210944 · Cited by 2,776
The Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in Purkinje Neurons and the Brain
Kriaucionis, S., & Heintz, N. (2009) · Science · doi:10.1126/science.1169786 · Cited by 2,700
The accessible chromatin landscape of the human genome
Thurman, R. E., Rynes, E., Humbert, R., Vierstra, J., Maurano, M. T., Haugen, E., Sheffield, N. C., Stergachis, A. B., Wang, H., Vernot, B., et al. (2012) · Nature · doi:10.1038/nature11232 · Cited by 2,679
Chromatin Structure: A Repeating Unit of Histones and DNA
Kornberg, R. D. (1974) · Science · doi:10.1126/science.184.4139.868 · Cited by 2,662
Chen, X., Han, X., Yuan, P., Fang, F., Huss, M., Vega, V. B., Wong, E., Orlov, Y. L., Zhang, W., Jiang, J., et al. (2008) · Cell · doi:10.1016/j.cell.2008.04.043 · Cited by 2,547
Genome-scale DNA methylation maps of pluripotent and differentiated cells
Meissner, A., Mikkelsen, T. S., Gu, H., Wernig, M., Hanna, J., Sivachenko, A., Zhang, X., Bernstein, B. E., Nusbaum, C., Jaffe, D. B., et al. (2008) · Nature · doi:10.1038/nature07107 · Cited by 2,536
Highly Integrated Single-Base Resolution Maps of the Epigenome in Arabidopsis
Lister, R., O’Malley, R. C., Tonti‐Filippini, J., Gregory, B. D., Berry, C. C., Millar, A. H., & Ecker, J. R. (2008) · Cell · doi:10.1016/j.cell.2008.03.029 · Cited by 2,424
Cancer-epigenetics comes of age
Jones, P. A., & Laird, P. W. (1999) · Nature Genetics · doi:10.1038/5947 · Cited by 2,358
Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma
Noushmehr, H., Weisenberger, D. J., Diefes, K., Phillips, H. S., Pujara, K., Berman, B. P., Pan, F., Pelloski, C. E., Sulman, E. P., Bhat, K. P., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.03.017 · Cited by 2,337
Irizarry, R. A., Ladd-Acosta, C., Wen, B., Wu, Z., Montano, C., Onyango, P., Cui, H., Gabo, K., Rongione, M., Webster, M., et al. (2009) · Nature Genetics · doi:10.1038/ng.298 · Cited by 2,177
EUKARYOTIC CYTOSINE METHYLTRANSFERASES
Goll, M. G., & Bestor, T. H. (2005) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.010904.153721 · Cited by 2,162
The Role of DNA Methylation in Mammalian Epigenetics
Jones, P. A., & Takai, D. (2001) · Science · doi:10.1126/science.1063852 · Cited by 2,125
The DNA methyltransferases of mammals
Bestor, T. H. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.16.2395 · Cited by 2,078
IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype
Turcan, S., Rohle, D., Goenka, A., Walsh, L. A., Fang, F., Yilmaz, E., Campos, C., Fabius, A. W. M., Lu, C., Ward, P. S., et al. (2012) · Nature · doi:10.1038/nature10866 · Cited by 1,974
Methylation-Induced Repression— Belts, Braces, and Chromatin
Bird, A. P., & Wolffe, A. P. (1999) · Cell · doi:10.1016/s0092-8674(00)81532-9 · Cited by 1,858
Global epigenomic reconfiguration during mammalian brain development
Lister, R., Mukamel, E. A., Nery, J. R., Urich, M., Puddifoot, C. A., Johnson, N. D., Lucero, J., Huang, Y., Dwork, A. J., Schultz, M. D., et al. (2013) · Science · doi:10.1126/science.1237905 · Cited by 1,830
Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene
Bell, A. C., & Felsenfeld, G. (2000) · Nature · doi:10.1038/35013100 · Cited by 1,746
Pioneer transcription factors: establishing competence for gene expression
Zaret, K. S., & Carroll, J. S. (2011) · Genes & Development · doi:10.1101/gad.176826.111 · Cited by 1,589
The power and the promise of DNA methylation markers
Laird, P. W. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1045 · Cited by 1,573
Identification and Characterization of a Family of Mammalian Methyl-CpG Binding Proteins
Hendrich, B., & Bird, A. P. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.11.6538 · Cited by 1,386
DNA-binding factors shape the mouse methylome at distal regulatory regions
Stadler, M. B., Murr, R., Burger, L., Ivanek, R., Lienert, F., Schöler, A., Nimwegen, E. V., Wirbelauer, C., Oakeley, E. J., Gaidatzis, D., et al. (2011) · Nature · doi:10.1038/nature10716 · Cited by 1,383
Insulator dysfunction and oncogene activation in IDH mutant gliomas
Flavahan, W. A., Drier, Y., Liau, B. B., Gillespie, S. M., Venteicher, A. S., Stemmer-Rachamimov, A. O., Suvà, M. L., & Bernstein, B. E. (2016) · Nature · doi:10.1038/nature16490 · Cited by 1,288
Epigenome-wide association studies for common human diseases
Rakyan, V. K., Down, T. A., Balding, D. J., & Beck, S. (2011) · Nature Reviews Genetics · doi:10.1038/nrg3000 · Cited by 1,288
Conservation and divergence of methylation patterning in plants and animals
Feng, S., Cokus, S. J., Zhang, X., Chen, P.-Y., Bostick, M., Goll, M. G., Hetzel, J., Jain, J., Strauss, S. H., Halpern, M. E., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002720107 · Cited by 1,285
Doi, A., Park, I., Wen, B., Murakami, P. N., Aryee, M. J., Irizarry, R. A., Herb, B. R., Ladd‐Acosta, C., Rho, J., Loewer, S., et al. (2009) · Nature Genetics · doi:10.1038/ng.471 · Cited by 1,201
DNA methylation and gene silencing in cancer
Baylin, S. B. (2005) · Nature Clinical Practice Oncology · doi:10.1038/ncponc0354 · Cited by 1,176
Chromatin remodelling during development
Ho, L., & Crabtree, G. R. (2010) · Nature · doi:10.1038/nature08911 · Cited by 1,114
Zhang, Y., Ng, H.-H., Erdjument-Bromage, H., Tempst, P., Bird, A., & Reinberg, D. (1999) · Genes & Development · doi:10.1101/gad.13.15.1924 · Cited by 1,103
DNA methylation in health and disease
Robertson, K. D., & Wolffe, A. P. (2000) · Nature Reviews Genetics · doi:10.1038/35049533 · Cited by 1,077
Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome
Yu, M., Hon, G. C., Szulwach, K. E., Song, C., Zhang, L., Kim, A., Li, X., Dai, Q., Shen, Y., Park, B., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.027 · Cited by 1,050
Diversity and Complexity in DNA Recognition by Transcription Factors
Badis, G., Berger, M., Philippakis, A. A., Talukder, S., Gehrke, A. R., Jaeger, S., Chan, E. T., Metzler, G., Vedenko, A., Chen, X., et al. (2009) · Science · doi:10.1126/science.1162327 · Cited by 1,031
Dynamic Readers for 5-(Hydroxy)Methylcytosine and Its Oxidized Derivatives
Spruijt, C. G., Gnerlich, F., Smits, A. H., Pfaffeneder, T., Jansen, P. W. T. C., Bauer, C., Münzel, M., Wagner, M., Müller, M., Khan, F., et al. (2013) · Cell · doi:10.1016/j.cell.2013.02.004 · Cited by 973
CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing
Shukla, S., Kavak, E., Gregory, M., Imashimizu, M., Shutinoski, B., Kashlev, M., Oberdoerffer, P., Sandberg, R., & Oberdoerffer, S. (2011) · Nature · doi:10.1038/nature10442 · Cited by 973
Quantitative Sequencing of 5-Methylcytosine and 5-Hydroxymethylcytosine at Single-Base Resolution
Booth, M. J., Branco, M. R., Ficz, G., Oxley, D., Krueger, F., Reik, W., & Balasubramanian, S. (2012) · Science · doi:10.1126/science.1220671 · Cited by 951
The essentials of DNA methylation
Bird, A. (1992) · Cell · doi:10.1016/0092-8674(92)90526-i · Cited by 948
MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system
Mellén, M., Ayata, P., Dewell, S., Kriaucionis, S., & Heintz, N. (2012) · Cell · doi:10.1016/j.cell.2012.11.022 · Cited by 943
Thymine DNA Glycosylase Can Rapidly Excise 5-Formylcytosine and 5-Carboxylcytosine
Maiti, A., & Drohat, A. C. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.c111.284620 · Cited by 825
Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming
Soufi, A., Garcia, M. F., Jaroszewicz, A., Osman, N., Pellegrini, M., & Zaret, K. S. (2015) · Cell · doi:10.1016/j.cell.2015.03.017 · Cited by 780
Valinluck, V. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh739 · Cited by 756
Effects of DNA methylation on DNA-binding proteins and gene expression
Tate, P. H., & Bird, A. P. (1993) · Current Opinion in Genetics & Development · doi:10.1016/0959-437x(93)90027-m · Cited by 737
The Honey Bee Epigenomes: Differential Methylation of Brain DNA in Queens and Workers
Lyko, F., Foret, S., Kucharski, R., Wolf, S., Falckenhayn, C., & Maleszka, R. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000506 · Cited by 727
Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain
Guo, J. U., Su, Y., Shin, J. H., Shin, J., Li, H., Xie, B., Zhong, C., Hu, S., Le, T., Fan, G., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3607 · Cited by 714
Self-citationHuman body epigenome maps reveal noncanonical DNA methylation variation
Schultz, M. D., He, Y., Whitaker, J. W., Hariharan, M., Mukamel, E. A., Leung, D., Rajagopal, N., Nery, J. R., Urich, M. A., Chen, H., et al. (2015) · Nature · doi:10.1038/nature14465 · Cited by 690
Pioneer transcription factors in cell reprogrammingPreprint
Iwafuchi, M., & Zaret, K. S. (2014) · Genes & Development · doi:10.1101/gad.253443.114 · Cited by 613
Nucleosome-Interacting Proteins Regulated by DNA and Histone Methylation
Bartke, T., Vermeulen, M., Xhemalce, B., Robson, S. C., Mann, M., & Kouzarides, T. (2010) · Cell · doi:10.1016/j.cell.2010.10.012 · Cited by 611
Variation in Homeodomain DNA Binding Revealed by High-Resolution Analysis of Sequence Preferences
Berger, M. F., Badis, G., Gehrke, A. R., Talukder, S., Philippakis, A. A., Peña-Castillo, L., Alleyne, T. M., Mnaimneh, S., Botvinnik, O. B., Chan, E. T., et al. (2008) · Cell · doi:10.1016/j.cell.2008.05.024 · Cited by 606
Quenneville, S., Verde, G., Corsinotti, A., Kapopoulou, A., Jakobsson, J., Offner, S., Baglivo, I., Pedone, P. V., Grimaldi, G., Riccio, A., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.08.032 · Cited by 606
CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease
Ohlsson, R., Renkawitz, R., & Lobanenkov, V. (2001) · Trends in Genetics · doi:10.1016/s0168-9525(01)02366-6 · Cited by 591
Disruption of DNA-methylation-dependent long gene repression in Rett syndrome
Gabel, H. W., Kinde, B., Stroud, H., Gilbert, C. S., Harmin, D. A., Kastan, N. R., Hemberg, M., Ebert, D. H., & Greenberg, M. E. (2015) · Nature · doi:10.1038/nature14319 · Cited by 569
Genome-wide Profiling of 5-Formylcytosine Reveals Its Roles in Epigenetic Priming
Song, C., Szulwach, K. E., Dai, Q., Fu, Y., Mao, S.-Q., Lin, L., Street, C., Li, Y., Poidevin, M., Wu, H., et al. (2013) · Cell · doi:10.1016/j.cell.2013.04.001 · Cited by 562
Iguchi-Ariga, S. M., & Schaffner, W. (1989) · Genes & Development · doi:10.1101/gad.3.5.612 · Cited by 559
Prendergast, G. C., Lawe, D., & Ziff, E. B. (1991) · Cell · doi:10.1016/0092-8674(91)90457-a · Cited by 558
GATA-4/5/6, a subfamily of three transcription factors transcribed in developing heart and gut.
Laverriere, A. C., MacNeill, C., Mueller, C., Poelmann, R. E., Burch, J. B., & Evans, T. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31636-8 · Cited by 558
Maunakea, A. K., Chepelev, I., Cui, K., & Zhao, K. (2013) · Cell Research · doi:10.1038/cr.2013.110 · Cited by 552
The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor
Prokhortchouk, A., Hendrich, B., Jørgensen, H., Ruzov, A., Wilm, M., Georgiev, G., Bird, A., & Prokhortchouk, E. (2001) · Genes & Development · doi:10.1101/gad.198501 · Cited by 533
Competition between DNA methylation and transcription factors determines binding of NRF1
Domcke, S., Bardet, A. F., Adrian Ginno, P., Hartl, D., Burger, L., & Schübeler, D. (2015) · Nature · doi:10.1038/nature16462 · Cited by 508
DNA methylation in Drosophila melanogaster
Lyko, F., Ramsahoye, B. H., & Jaenisch, R. (2000) · Nature · doi:10.1038/35046205 · Cited by 501
Genome-wide Analysis Reveals TET- and TDG-Dependent 5-Methylcytosine Oxidation Dynamics
Shen, L., Wu, H., Diep, D., Yamaguchi, S., D’Alessio, A. C., Fung, H.-L., Zhang, K., & Zhang, Y. (2013) · Cell · doi:10.1016/j.cell.2013.04.002 · Cited by 497
The Discovery of 5‐Formylcytosine in Embryonic Stem Cell DNA
Pfaffeneder, T., Hackner, B., Truß, M., Münzel, M., Müller, M., Deiml, C. A., Hagemeier, C., & Carell, T. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201103899 · Cited by 483
Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues
Hon, G. C., Rajagopal, N., Shen, Y., McCleary, D. F., Yue, F., Dang, M. D., & Ren, B. (2013) · Nature Genetics · doi:10.1038/ng.2746 · Cited by 477
Mechanisms and models of somatic cell reprogramming
Buganim, Y., Faddah, D. A., & Jaenisch, R. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3473 · Cited by 467
Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities
Cairns, R. A., & Mak, T. W. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0083 · Cited by 452
CpG methylation inhibits proenkephalin gene expression and binding of the transcription factor AP-2
Comb, M., & Goodman, H. M. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.13.3975 · Cited by 422
The methyl-CpG binding domain and the evolving role of DNA methylation in animals
Hendrich, B., & Tweedie, S. (2003) · Trends in Genetics · doi:10.1016/s0168-9525(03)00080-5 · Cited by 417
Brinkman, A. B., Gu, H., Bartels, S. J. J., Zhang, Y., Matarese, F., Simmer, F., Marks, H., Bock, C., Gnirke, A., Meissner, A., et al. (2012) · Genome Research · doi:10.1101/gr.133728.111 · Cited by 413
N-CoR Mediates DNA Methylation-Dependent Repression through a Methyl CpG Binding Protein Kaiso
Yoon, H.-G., Chan, D. W., Reynolds, A. B., Qin, J., & Wong, J. (2003) · Molecular Cell · doi:10.1016/j.molcel.2003.08.008 · Cited by 408
Hu, S., Xie, Z., Onishi, A., Yu, X., Jiang, L., Lin, J., Rho, H., Woodard, C. L., Wang, H., Jeong, J. S., et al. (2009) · Cell · doi:10.1016/j.cell.2009.08.037 · Cited by 390
Self-citationMethylation-Dependent and -Independent Genomic Targeting Principles of the MBD Protein Family
Baubec, T., Ivánek, R., Lienert, F., & Schübeler, D. (2013) · Cell · doi:10.1016/j.cell.2013.03.011 · Cited by 365
DNA methylation presents distinct binding sites for human transcription factors
Hu, S., Wan, J., Su, Y., Song, Q., Zeng, Y., Nguyen, H. N., Shin, J., Cox, E., Rho, H. S., Woodard, C., et al. (2013) · eLife · doi:10.7554/elife.00726 · Cited by 349
Self-citationNagarajan, R., Hogart, A., Gwye, Y., Martin, M. R., & LaSalle, J. M. (2006) · Epigenetics · doi:10.4161/epi.1.4.3514 · Cited by 347
MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system
Mellén, M., Ayata, P., Dewell, S. B., Kriaučionis, S., & Heintz, N. (2013) · Epigenetics & Chromatin · doi:10.1186/1756-8935-6-s1-p52 · Cited by 345
Sensitive digital quantification of DNA methylation in clinical samples
Li, M., Chen, W.-D., Papadopoulos, N., Goodman, S. N., Bjerregaard, N. C., Laurberg, S., Levin, B., Juhl, H., Arber, N., Moinova, H., et al. (2009) · Nature Biotechnology · doi:10.1038/nbt.1559 · Cited by 341
Iurlaro, M., Ficz, G., Oxley, D., Raiber, E., Bachman, M., Booth, M. J., Andrews, S., Balasubramanian, S., & Reik, W. (2013) · Genome biology · doi:10.1186/gb-2013-14-10-r119 · Cited by 321
CTCF maintains differential methylation at the Igf2/H19 locus
Schoenherr, C. J., Levorse, J. M., & Tilghman, S. M. (2003) · Nature Genetics · doi:10.1038/ng1057 · Cited by 320
GATA transcription factors as potentiators of gut endoderm differentiation
Bossard, P., & Zaret, K. S. (1998) · Development · doi:10.1242/dev.125.24.4909 · Cited by 313
Role of DNA Methylation in Modulating Transcription Factor Occupancy
Maurano, M. T., Wang, H., John, S., Shafer, A., Canfield, T., Lee, K., & Stamatoyannopoulos, J. A. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.07.024 · Cited by 281
Role of an adenovirus E2 promoter binding factor in E1A-mediated coordinate gene control.
Kovesdi, I., Reichel, R., & Nevins, J. R. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.8.2180 · Cited by 278
Bestor, T. H. (1990) · Philosophical transactions of the Royal Society of London. Series B, Biological sciences · doi:10.1098/rstb.1990.0002 · Cited by 238
Kinde, B., Gabel, H. W., Gilbert, C. S., Griffith, E. C., & Greenberg, M. E. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1411269112 · Cited by 236
Rishi, V., Bhattacharya, P., Chatterjee, R., Rozenberg, J. M., Zhao, J., Glass, K., FitzGerald, P. C., & Vinson, C. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008688107 · Cited by 225
He, H. H., Meyer, C. A., Hu, S. S., Chen, M.-W., Zang, C., Liu, Y., Rao, P. K., Fei, T., Xu, H., Long, H., et al. (2014) · Nature Methods · doi:10.1038/nmeth.2762 · Cited by 218
Cross-talk between Site-specific Transcription Factors and DNA Methylation States
Blattler, A., & Farnham, P. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.r113.512517 · Cited by 210
Statham, A. L., Robinson, M. D., Song, J. Z., Coolen, M. W., Stirzaker, C., & Clark, S. J. (2012) · Genome Research · doi:10.1101/gr.132076.111 · Cited by 208
Methyl CpG binding proteins: coupling chromatin architecture to gene regulation
Wade, P. A. (2001) · Oncogene · doi:10.1038/sj.onc.1204340 · Cited by 203
Saito, M., & Ishikawa, F. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203455200 · Cited by 189
Epigenetic phenomena in filamentous fungi: useful paradigms or repeat-induced confusion?
Selker, E. U. (1997) · Trends in Genetics · doi:10.1016/s0168-9525(97)01201-8 · Cited by 187
Liu, J. K., DiPersio, C. M., & Zaret, K. S. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.2.773 · Cited by 168
Wan, J., Oliver, V. F., Wang, G., Zhu, H., Zack, D. J., Merbs, S. L., & Qian, J. (2015) · BMC Genomics · doi:10.1186/s12864-015-1271-4 · Cited by 165
Self-citationProbing DNA shape and methylation state on a genomic scale with DNase I
Lazarovici, A., Zhou, T., Shafer, A., Dantas Machado, A. C., Riley, T. R., Sandstrom, R., Sabo, P. J., Lu, Y., Rohs, R., Stamatoyannopoulos, J. A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1216822110 · Cited by 162
A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A
Jiang, Y., Sahoo, T., Michaelis, R. C., Bercovich, D., Bressler, J., Kashork, C. D., Liu, Q., Shaffer, L. G., Schroer, R. J., Stockton, D. W., et al. (2004) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.30297 · Cited by 159
Wu, H., Wu, X., Shen, L., & Zhang, Y. (2014) · Nature Biotechnology · doi:10.1038/nbt.3073 · Cited by 157
Bisulfite-free, base-resolution analysis of 5-formylcytosine at the genome scale
Xia, B., Han, D., Lu, X., Sun, Z., Zhou, A., Yin, Q., Zeng, H., Liu, M., Jiang, X., Xie, W., et al. (2015) · Nature Methods · doi:10.1038/nmeth.3569 · Cited by 153
Strogantsev, R., Krueger, F., Yamazawa, K., Shi, H., Gould, P., Goldman-Roberts, M., McEwen, K., Sun, B., Pedersen, R., & Ferguson-Smith, A. C. (2015) · Genome Biology · doi:10.1186/s13059-015-0672-7 · Cited by 152
Li, J. J., Jiang, C., Brown, J., Huang, H., & Bickel, P. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113972108 · Cited by 140
Takayama, S., Dhahbi, J. M., Roberts, A., Mao, G., Heo, S., Pachter, L. S., Martin, D. I. K., & Boffelli, D. (2014) · Genome Research · doi:10.1101/gr.162412.113 · Cited by 130
An atomic model of Zfp57 recognition of CpG methylation within a specific DNA sequencePreprint
Liu, Y., Toh, H., Sasaki, H., Zhang, X., & Cheng, X. (2012) · Genes & Development · doi:10.1101/gad.202200.112 · Cited by 128
Buck-Koehntop, B. A., Stanfield, R. L., Ekiert, D. C., Martinez-Yamout, M. A., Dyson, H. J., Wilson, I. A., & Wright, P. E. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1213726109 · Cited by 128
Charlet, J., Duymich, C. E., Lay, F. D., Mundbjerg, K., Dalsgaard Sørensen, K., Liang, G., & Jones, P. A. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.03.033 · Cited by 128
Neri, F., Incarnato, D., Křepelová, A., Rapelli, S., Anselmi, F., Parlato, C., Medana, C., Bello, F. D., & Oliviero, S. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.01.008 · Cited by 127
Jeon, J., Choi, J., Lee, G.-W., Park, S., Huh, A., Dean, R. A., & Lee, Y. (2015) · Scientific Reports · doi:10.1038/srep08567 · Cited by 126
Mann, I. K., Chatterjee, R., Zhao, J., He, X., Weirauch, M. T., Hughes, T. R., & Vinson, C. (2013) · Genome Research · doi:10.1101/gr.146654.112 · Cited by 126
Evolving insights on how cytosine methylation affects protein-DNA binding
Dantas Machado, A. C., Zhou, T., Rao, S., Goel, P., Rastogi, C., Lazarovici, A., Bussemaker, H. J., & Rohs, R. (2015) · Briefings in Functional Genomics · doi:10.1093/bfgp/elu040 · Cited by 124
PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine
Fujiki, K., Shinoda, A., Kano, F., Sato, R., Shirahige, K., & Murata, M. (2013) · Nature Communications · doi:10.1038/ncomms3262 · Cited by 123
Histone modifications, DNA methylation, and Schizophrenia
Gavin, D. P., & Sharma, R. P. (2010) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2009.10.010 · Cited by 121
Inamdar, N. M., Ehrlich, K. C., & Ehrlich, M. (1991) · Plant Molecular Biology · doi:10.1007/bf00036811 · Cited by 120
Lopes, E. C., Valls, E., Figueroa, M. E., Mazur, A., Meng, F.-G., Chiosis, G., Laird, P. W., Schreiber-Agus, N., Greally, J. M., Prokhortchouk, E., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0344 · Cited by 119
Bahar Halpern, K., Vana, T., & Walker, M. D. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.573469 · Cited by 119
Structural basis for Klf4 recognition of methylated DNA
Liu, Y., Olanrewaju, Y. O., Zheng, Y., Hashimoto, H., Blumenthal, R. M., Zhang, X., & Cheng, X. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku134 · Cited by 99
Sun, Z., Dai, N., Borgaro, J. G., Quimby, A., Sun, D., Junior, I. R. C., Zheng, Y., Zhu, Z., & Guan, S. (2015) · Molecular Cell · doi:10.1016/j.molcel.2014.12.035 · Cited by 86
ZBTB33 binds unmethylated regions of the genome associated with actively expressed genes
Blattler, A., Yao, L., Wang, Y., Ye, Z., Jin, V. X., & Farnham, P. J. (2013) · Epigenetics & Chromatin · doi:10.1186/1756-8935-6-13 · Cited by 82
Krebs, A. R., Dessus-Babus, S., Burger, L., & Schübeler, D. (2014) · eLife · doi:10.7554/elife.04094 · Cited by 81
The orphan nuclear receptor GCNF recruits DNA methyltransferase for Oct-3/4 silencing
Sato, N., Kondo, M., & Arai, K.-I. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.04.007 · Cited by 80
Evolutionary Divergence of Monocot and Dicot Methyl-CpG-Binding Domain Proteins
Springer, N. M., & Kaeppler, S. M. (2005) · PLANT PHYSIOLOGY · doi:10.1104/pp.105.060566 · Cited by 79
DNA Methylation in Drosophila—A Critical Evaluation
Krauß, V., & Reuter, G. (2011) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-387685-0.00003-2 · Cited by 66
Hantusch, B., Kalt, R., Krieger, S., Puri, C., & Kerjaschki, D. (2007) · BMC Molecular Biology · doi:10.1186/1471-2199-8-20 · Cited by 63
Bednarik, D. P., Duckett, C. S., Kim, S. U., Perez, V. L., Griffis, K., Guenthner, P. C., & Folks, T. M. (1991) · PubMed · Cited by 62
Protein Binding Protects Sites on Stable Episomes and in the Chromosome from De Novo Methylation
Han, L., Lin, I. G., & Hsieh, C. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.10.3416-3424.2001 · Cited by 62
Zhang, X.-Y., Asiedu, C. K., Supakar, P. C., Khan, R., Ehrlich, K. C., & Ehrlich, M. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.21.6253 · Cited by 54
Khrapunov, S. N., Warren, C. L., Cheng, H., Berko, E. R., Greally, J. M., & Brenowitz, M. D. (2014) · Biochemistry · doi:10.1021/bi500424z · Cited by 51
Wan, J., Oliver, V. F., Zhu, H., Zack, D. J., Qian, J., & Merbs, S. L. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt652 · Cited by 49
Self-citationYu, D.-H., Ware, C., Waterland, R. A., Zhang, J., Chen, M.-H., Gadkari, M., Kunde-Ramamoorthy, G., Nosavanh, L. M., & Shen, L. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01124-12 · Cited by 48
Gao, F., Ji, G., Gao, Z., Han, X., Ye, M., Yuan, Z., Luo, H., Huang, X., Natarajan, K., Wang, J., et al. (2014) · Genomics · doi:10.1016/j.ygeno.2013.12.006 · Cited by 47
Activation of a Methylated Promoter Mediated by a Sequence-specific DNA-binding Protein, RFX
Niesen, M. I., Osborne, A. R., Yang, H., Rastogi, S., Chellappan, S., Cheng, J. Q., Boss, J. M., & Blanck, G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504633200 · Cited by 42
Tippin, D. B., & Sundaralingam, M. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.0945 · Cited by 42
Karlsson, Q. H., Schelcher, C., Verrall, E., Petosa, C., & Sinclair, A. J. (2008) · PLoS Pathogens · doi:10.1371/journal.ppat.1000005 · Cited by 39
Falzon, M., & Kuff, E. L. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.1.117 · Cited by 37
Ehrlich, K. C., Cary, J. W., & Ehrlich, M. (1992) · Gene · doi:10.1016/0378-1119(92)90726-6 · Cited by 30
Liu, S., Zhang, H., Dai, J., Hu, S., Pino, I., Eichinger, D. J., Lyu, H., & Zhu, H. (2014) · mAbs · doi:10.4161/19420862.2014.985919 · Cited by 29
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Qin, S., Zhang, B., Tian, W., Gu, L., Lu, Z., & Deng, D. (2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.1000-9604.2015.04.03 · Cited by 14
He, X., Fütterer, J., & Hohn, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m006653200 · Cited by 9
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Metadata
- Authors
- Zhu, H., Wang, G., & Qian, J.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Zhu, Heng
- Qian, Jiang
- Venue
- Nature Reviews Genetics
- Published
- 2016-08-01
- Volume
- 17
- Issue
- 9
- Pages
- 551-565
- ISSN
- 1471-0056 (ISSN-L)
- 1471-0064
- PMC
- PMC5559737
- OpenAlex
- W2494121918
- Semantic Scholar
- 6dee1bc645a95ab7b9afe8a303d0b916cc74f4b3
- Cited by
- 649
- References
- 146
- Citations by year
- 2026: 35 · 2025: 46 · 2024: 81 · 2023: 53 · 2022: 107 · 2021: 102 · 2020: 74 · 2019: 62 · 2018: 44 · 2017: 38 · 2016: 7
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Reviews Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (R01EY024580, R01EY023188)
- National Institute of General Medical Sciences (R01GM111514)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- DNA methylation, transcription factors, methyl-CpG binding domain, protein-DNA interactions, methylated DNA, differentially methylated sites, aberrant DNA methylation, epigenetic regulation, cancer epigenetics, human development
- MeSH terms
- DNA, DNA-Binding Proteins, Humans, Transcription Factors, Transcription, Genetic, DNA Methylation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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