Transcription factors as readers and effectors of DNA methylation

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.”

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).”

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”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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

In the paper

“approximately 6.7% of the mouse genome is differentially methylated, mostly at distal cis-regulatory regions77.”

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

In the paper

“the DNA probes used in this approach are typically generic and, therefore, sequence specificity of observed interactions remains elusive.”

In the paper

“prior knowledge of a candidate TF is required because it can be cumbersome to survey an entire TF family.”

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.”

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

In the paper

“A subsequent validation assay showed that some of these TFs indeed bind to methylated DNA in vivo and regulate gene expression53.”

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

In the paper

“A separate study suggested that an arginine and glutamate pair in KLF4 recognizes the mCpG site68.”

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

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.”

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

In the paper

“it requires prior knowledge of mCpG-binding proteins and the availability of antibodies that are directed against the proteins of interest.”

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.”

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

In the paper

“These methylation regions are overrepresented in DHSs and are evolutionarily conserved”

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

In the paper

“Insertion of the binding site induced CTCF binding and resulted in a reduced methylation level in local genomic regions.”

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

In the paper

“Methylation in promoters is often considered the hallmark for gene repression99.”

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

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.”

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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

In the paper

“The mCpG-binding protein KLF4 was also shown to be a pioneer factor105,111.”

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

In the paper

“Pioneer TFs are a unique subset of TFs that drive these chromatin changes.”

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

In the paper

“Chromatin organization is dynamic, and the different types of chromatin can change from one form to another during development or differentiation104”

What the sources say

• Not checked yetcites [104] Ho, L. & Crabtree, G. R. Chromatin remodelling during development. Nature 463, 474–484 (2010). source

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.”

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

In the paper

“Differences in chromatin states will either create or eliminate TF binding sites and thus lead to differential TF binding.”

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.”

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

In the paper

“Although CTCF motifs were significantly enriched in differentially methylated regions associated with alternative splicing, other motifs were also enriched”

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

In the paper

“IDH mutant gliomas have been shown to exhibit hypermethylation at CTCF binding sites, which leads to a reduction in CTCF binding”

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

In the paper

“Many studies have shown that aberrant DNA methylation is associated with various human diseases, including some types of cancer19–21.”

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

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”

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

In the paper

“loss of CTCF in topologically associated domains removed the domain boundary and caused aberrant gene activation117.”

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

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.”

What the sources say

• Not checked yetcites [118] Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008). source
• Not checked yetcites [119] Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009). source

In the paper

“Of note, this new concept does not refute the conventional view that most TFs do not interact with methylated DNA.”

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.”