Structural basis for Klf4 recognition of methylated DNA
Open accessAbstract
Transcription factor Krüppel-like factor 4 (Klf4), one of the factors directing cellular reprogramming, recognizes the CpG dinucleotide (whether methylated or unmodified) within a specific G/C-rich sequence. The binding affinity of the mouse Klf4 DNA-binding domain for methylated DNA is only slightly stronger than that for an unmodified oligonucleotide. The structure of the C-terminal three Krüppel-like zinc fingers (ZnFs) of mouse Klf4, in complex with fully methylated DNA, was determined at 1.85 Å resolution. An arginine and a glutamate interact with the methyl group. By comparison with two other recently characterized structures of ZnF protein complexes with methylated DNA, we propose a common principle of recognition of methylated CpG by C2H2 ZnF proteins, which involves a spatially conserved Arg-Glu pair.
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A bulky methyl group in the major groove leads to subtle widening of the major groove and narrowing of the minor groove.
“the presence of a bulky methyl group in the major groove leads to a subtle widening of the major groove and a subtle narrowing of the minor groove.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [68]
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BackgroundInfluentialSelf-citationKaiso Regulates DNA Methylation Homeostasis
Kaplun, D., Starshin, A., Сергеевич, Ш. Ф., Gainova, K., Filonova, G. E., Zhigalova, N., Mazur, A. M., Prokhortchouk, E., & Zhenilo, S. V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147587 · Cited by 44 · see citing works
“It was shown by X-ray diffraction data that the three-dimensional structure of Kaiso-mCpG DNA interaction is the same as KLF4-mCpG interaction [17].”
BackgroundGillinder, K. R., Ilsley, M. D., Nébor, D., Sachidanandam, R., Lajoie, M., Magor, G. W., Tallack, M. R., Bailey, T. L., Landsberg, M. J., Mackay, J. P., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1014 · Cited by 44 · see citing works
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“5-fold) than that of the unmodified DNA, and each oxidation event, from 5mC to 5hmC to 5fC to 5caC, results in progressively weaker binding (by factors of 2, 3, and 6, respectively) (57).”
BackgroundSelf-citationStructural insights into the recognition of γ-globin gene promoter by BCL11A
Yang, Y., Xu, Z. Z., He, C. J., Zhang, B., Shi, Y., & Li, F. (2019) · Cell Research · doi:10.1038/s41422-019-0221-0 · Cited by 40 · see citing works
Updated understanding of the protein–DNA recognition code used by C2H2 zinc finger proteins
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“Each finger has an Asp at −5, which is almost always associated with an Arg at −7 (additional examples include Wilms tumor protein WT1 [76] and Krüppel-like factor Klf4 [77]) (Figure 3l).”
Self-citationGenome-wide bisulphite-sequencing reveals organ-specific methylation patterns in chickpea
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Structural basis for human ZBTB7A action at the fetal globin promoter
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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript interaction has been previously observed in Lys328 of ZNF410 and Lys413 of KLF4 (Lan et al., 2021; Liu et al., 2014).”
BackgroundInfluentialSelf-citationRole of the reprogramming factor KLF4 in blood formation
Park, C. S., Shen, Y., Lewis, A. H., & Lacorazza, H. D. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.1ru1215-539r · Cited by 34 · see citing works
“This property of recognizing methylated and nonmethylated cytosines can be decoupled by protein mutagenesis of the zinc finger domains [21, 22].”
BackgroundDNA Methylation and Chromatin: Role(s) of Methyl-CpG-Binding Protein ZBTB38
de Dieuleveult, M., & Miotto, B. (2018) · Epigenetics Insights · doi:10.1177/2516865718811117 · Cited by 34 · see citing works
GADD45 promotes locus-specific DNA demethylation and 2C cycling in embryonic stem cellsPreprint
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“The most prominent hit in all DMRs was Klf5, a possible reader of methylated DNA (Spruijt et al. 2013; Liu et al. 2014), which promotes the pluripotent ESC state and is required for trophectoderm development (Ema et al.”
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Characterization of How DNA Modifications Affect DNA Binding by C2H2 Zinc Finger Proteins
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“Of the >300 human or mouse KRAB-ZnF proteins examined, the number of tandem ZnFs ranges from 3 to 35, with a mode of around 11–13 fingers (Liu, Zhang, et al., 2013; Fig.”
InfluentialSelf-citationIlsley, M. D., Huang, S., Magor, G. W., Landsberg, M. J., Gillinder, K. R., & Perkins, A. C. (2019) · BMC Genomics · doi:10.1186/s12864-019-5805-z · Cited by 32 · see citing works
Hudson, N. O., Whitby, F. G., & Buck‐Koehntop, B. A. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.005147 · Cited by 28 · see citing works
“Intriguingly, the majority of ZF MBP–methylated DNA complex structures solved to date have one mC within the mCpG palindrome that has a hydration shell around its methyl group (20, 23, 24, 26).”
BackgroundDNA methylation and the core pluripotency network
Shanak, S., & Helms, V. (2020) · Developmental Biology · doi:10.1016/j.ydbio.2020.06.001 · Cited by 28 · see citing works
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“83,84 85-87 In addition, our studies demonstrate that the presence of a KLF protein with a change that significantly alters binding is detrimental and not biologically well tolerated within the cell, leading to a significantly altered genetic output even in the company of the WT.”
Structural basis for effects of CpA modifications on C/EBPβ binding of DNA
Yang, J., Horton, J. R., Wang, D., Ren, R., Li, J., Sun, D., Huang, Y., Zhang, X., Blumenthal, R., & Cheng, X. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1264 · Cited by 27 · see citing works
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Distinctive Klf4 mutants determine preference for DNA methylation status
Hashimoto, H., Wang, D., Steves, A. N., Jin, P., Blumenthal, R., Zhang, X., & Cheng, X. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw774 · Cited by 27 · see citing works
“In the structure of the Klf4 bound to methylated DNA (20), the methyl group of 5mC in the recognition strand makes a van der Waals contact with the aliphatic carbon C (cid:4) and forms a weak C-H...”
InfluentialSelf-citationThe C-Terminal Zinc Fingers of ZBTB38 are Novel Selective Readers of DNA Methylation
Pozner, A., Hudson, N. O., Trewhella, J., Terooatea, T. W., Miller, S. A., & Buck‐Koehntop, B. A. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.12.014 · Cited by 25 · see citing works
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“[38] reported another sequencemotif and binding constants.”
Cys2His2 Zinc Finger Methyl-CpG Binding Proteins: Getting a Handle on Methylated DNA
Hodges, A. J., Hudson, N. O., & Buck‐Koehntop, B. A. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.09.012 · Cited by 23 · see citing works
Anuja, K., Kar, M., Chowdhury, A. R., Shankar, G., Padhi, S., Roy, S., Akhter, Y., Rath, A. K., & Banerjee, B. (2020) · International Journal of Radiation Biology · doi:10.1080/09553002.2020.1721609 · Cited by 23 · see citing works
“in ZnF2 domain around the amino acid positions Arg 443/ Asp 445/Glu 446/Arg 449 (Liu et al. 2014).”
BackgroundAi, Z., Shao, J., Wu, Y., Yu, M., Du, J., Shi, X., Shi, X., Zhang, Y., & Guo, Z. (2016) · PLoS ONE · doi:10.1371/journal.pone.0150936 · Cited by 22 · see citing works
“This is because two recent studies have suggested that Klf4, functions as a 5-methylcytosine (5mC) reader, binding to specific methylated and/or unmethylated elements in mESCs [38, 39].”
Background22 Evolving insights on how cytosine methylation affects protein-DNA binding
Rao, S., Machado, A. C. D., Zhou, T., Rastogi, C., Bussemaker, H. J., & Rohs, R. (2015) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2015.1032562 · Cited by 21 · see citing works
“Comparison of the Klf4 binding sites with and without cytosine methylation [92, 93] clearly showed the impact of the cytosine methyl group on hydrophobic contacts (Figure 4A and B).”
BackgroundInfluentialZhou, Z., Huang, F., Shrivastava, I. H., Zhu, R., Luo, A., Hottiger, M. O., Bahar, İ., Liu, Z., Cristofanilli, M., & Wan, Y. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.202012391 · Cited by 19 · see citing works
“This notion is supported by recent reports that protein methylation plays an important role in rendering KLF4 to specific DNA motifs (Hu et al, 2013; Liu et al, 2014).”
BackgroundPowis, Z., Petrik, I., Cohen, J. S., Escolar, D. M., Burton, J. E., van Ravenswaaij‐Arts, C. M. A., Sival, D. A., Stegmann, A. P. A., Kleefstra, T., Pfundt, R., et al. (2017) · Clinical Genetics · doi:10.1111/cge.13198 · Cited by 18 · see citing works
“2 | Structural analysis The structure of KLF7 with bound DNA was modeled based on the crystal structure of KLF4 bound to DNA (PDB: 4M9E).(18) The Zinc finger domains of KLF4 and KLF7 share 73% identity, with 100% conservation observed at DNA interacting residues.”
BackgroundContext-dependent CpG methylation directs cell-specific binding of transcription factor ZBTB38
Marchal, C., Defossez, P., & Miotto, B. (2022) · Epigenetics · doi:10.1080/15592294.2022.2111135 · Cited by 16 · see citing works
“Similarly, less than 5% of EGR-1 and KLF4 binding sites in human cells actually contain fully methylated CpG sites [20,21,28].”
BackgroundVasotocin and the origins of the vasopressin/oxytocin receptor gene family
Mayasich, S. A., & Clarke, B. L. (2020) · Vitamins and hormones · doi:10.1016/bs.vh.2019.08.018 · Cited by 16 · see citing works
Ren, R., Horton, J. R., Chen, Q., Yang, J., Liu, B., Huang, Y., Blumenthal, R., Zhang, X., & Cheng, X. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.102885 · Cited by 15 · see citing works
“The cross-strand interaction of Lys396–G1 has been previously observed in Lys413 of KLF4 and Lys328 of ZNF410 (38, 39).”
BackgroundSelf-citationSurface condensation of a pioneer transcription factor on DNAPreprint
Morín, J. A., Wittmann, S., Choubey, S., Kłosin, A., Golfier, S., Hyman, A. A., Jülicher, F., & Grill, S. W. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.09.24.311712 · Cited by 15 · see citing works
KLF feedback loops in innate immunity
Salmon, J. M., Adams, H. R., Magor, G. W., & Perkins, A. C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1606277 · Cited by 13 · see citing works
“Mouse genetic studies have demonstrated critical roles for KLFs 5, 2, 6 and 4 at different stages of embryo, or early post-natal development (39 – 43).”
Nikolova, E. N., Stanfield, R. L., Dyson, H. J., & Wright, P. E. (2020) · Biochemistry · doi:10.1021/acs.biochem.0c00253 · Cited by 14 · see citing works
Structurally-Discovered KLF4 Variants Accelerate and Stabilize Reprogramming to Pluripotency
Borisova, E., Nishimura, K., An, Y., Takami, M., Li, J., Song, D., Matsuo‐Takasaki, M., Luijkx, D. G., Aizawa, S., Kuno, A., et al. (2020) · iScience · doi:10.1016/j.isci.2021.103525 · Cited by 16 · see citing works
Loss-of-function variants in KLF4 underlie autosomal dominant palmoplantar keratoderma
Malovitski, K., Sarig, O., Assaf, S., Mohamad, J., Malki, L., Bergson, S., Peled, A., Eskin‐Schwartz, M., Gat, A., Pavlovsky, M., et al. (2022) · Genetics in Medicine · doi:10.1016/j.gim.2022.01.009 · Cited by 13 · see citing works
Multi-omic analyses of m5C readers reveal their characteristics and immunotherapeutic proficiency
Xu, R. J., Wang, Y., & Kuang, Y. (2024) · Scientific Reports · doi:10.1038/s41598-024-52110-7 · Cited by 13 · see citing works
“Interestingly, the m5C binding mode of YBX1 is similar to DNA m5C recognition by certain transcription factors 75,76 .”
BackgroundProteins That Read DNA Methylation
Liu, K., Shimbo, T., Song, X., Wade, P. A., & Min, J. (2022) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-11454-0_11 · Cited by 13 · see citing works
Kaiso Gene Knockout Promotes Somatic Cell Reprogramming
Kaplun, D., Fok, R., Korostina, V. S., Prokhortchouk, E., & Zhenilo, S. V. (2019) · Biochemistry (Moscow) · doi:10.1134/s0006297919030106 · Cited by 11 · see citing works
Zhang, X., Blumenthal, R., & Cheng, X. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae832 · Cited by 9 · see citing works
“H) ( 81 , 92 , 107 , 108 ).”
BackgroundSelf-citationKrüppel-like factor 4 promotes survival and expansion in acute myeloid leukemia cells
Lewis, A. H., Bridges, C. S., Punia, V. S., Cooper, A. F. J., Puppi, M., & Lacorazza, H. D. (2021) · Oncotarget · doi:10.18632/oncotarget.27878 · Cited by 9 · see citing works
“Further analysis of KLF4 transcript levels and DNA methylation revealed no significant correlation in AML while the levels of KLF4 correlated with gene methylation in other types of cancer (Figure 1B).”
BackgroundInfluentialReading cytosine modifications within chromatin
Mahé, E. A., Madigou, T., & Salbert, G. (2018) · Transcription · doi:10.1080/21541264.2017.1406435 · Cited by 9 · see citing works
“also implicated in 5mC interaction with KAISO, another Zinc-finger protein [30,31].”
BackgroundVariants in KLF4 affecting residue Asp441 cause an autosomal dominant syndromic ichthyosis
Wang, Z., Liu, J., Wechsberg, O., Liang, L., Keegan, C. E., Sloan-Heggen, C., Mo, Y., Luo, Y., Wang, H., & Lin, Z. (2025) · British Journal of Dermatology · doi:10.1093/bjd/ljaf062 · Cited by 8 · see citing works
Thapa, B., Adhikari, N. P., Tiwari, P. B., & Chapagain, P. P. (2022) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.2c01294 · Cited by 7 · see citing works
The old and the new: DNA and RNA methylation in normal and malignant hematopoiesis
Guirguis, A. A., Liddicoat, B., & Dawson, M. A. (2020) · Experimental Hematology · doi:10.1016/j.exphem.2020.09.193 · Cited by 6 · see citing works
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Design and Application of 6mA-Specific Zinc-Finger Proteins for the Readout of DNA Methylation
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Long noncoding RNA TUG1 regulates smooth muscle cell differentiation via KLF4-myocardin axis
Bharadhwaj, R. A., & Kumarswamy, R. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00275.2023 · Cited by 5 · see citing works
Heterogeneous condensates of transcription factors in embryonic stem cells: Molecular simulations
Mizutani, A., Tan, C., Sugita, Y., & Takada, S. (2025) · Biophysical Journal · doi:10.1016/j.bpj.2025.04.001 · Cited by 4 · see citing works
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Epigenetic Rewiring of Protein Kinase Signalling in T-Cell Acute Lymphoblastic Leukaemia
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“…mechanism is based on its capacity to both methylate and de-methylate GC-rich sequences or exhibit protein-to-protein interactions with proteins bound to gene regulatory elements, resulting in the recruitment of coactivators or corepressors depending on the cell context or environment [186,187].”
Region‐specific DNA hydroxymethylation along the malignant progression of IDH ‐mutant gliomas
Hana, T., Mukasa, A., Nomura, M., Nagae, G., Yamamoto, S., Tatsuno, K., Ueda, H., Fukuda, S., Umeda, T., Tanaka, S., et al. (2024) · Cancer Science · doi:10.1111/cas.16127 · Cited by 2 · see citing works
Epigenetics in infectious disease
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Structural analysis of the BisI family of modification dependent restriction endonucleases
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“Other examples of proteins that accept both 5mC:G and T:A pairs are Kaiso ( 75 ), Klf4 ( 76 ,77 ), and the activator protein 1 (AP-1) ( 78 ).”
GenomicLayers: sequence-based simulation of epi-genomes
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Neuroepigenomics and Human Disease
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Backbone 1H, 13C, and 15N NMR resonance assignments of the Krüppel-like factor 4 activation domain
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Heterogenous organization in condensates of multiple transcription factors in embryonic stem cellsPreprint
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“Proteins such as Kaiso, Zfp57, Klf4, Egr1, and WT1, which are 5mC binding proteins [35,37,38,42], recognize thymine in the same way as they recognize 5mC.”
MNase stratification reveals heterogeneous 5hmC in naive B cellsPreprint
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“For instance, KLF4 can recognize or even prefer methylated CpG in its binding site, whereas numerous other TFs, including other KLFs and IRFs, are inhibited by CpG methylation 22,23 .”
Epigenetic Regulation in Macrophage Functional Remodeling
Yang, Y.-Q., Hu, Y.-Y., Qin, H., & Zhao, J.-L. (2026) · Genetics. · doi:10.5772/intechopen.1012974
DNA Methylation Readers in Biosensing Strategies
Aphrham, S., Verheijden, M. L., & Huskens, J. (2026) · ACS Sensors · doi:10.1021/acssensors.6c01631
KLF4/MLL3 complex axis drives NRBP2 transcription to eliminate acute myeloid leukemia cells
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Gene regulatory mechanisms downstream of DNA methylation
Buckley, T. J., Burns, M. J., Jarry, L., Wang, S., Soe, S. M. L., & Jacobsen, S. E. (2026) · Nature Reviews Genetics · doi:10.1038/s41576-026-01008-3
DALAI, W., Saeki, K., Jiya, W., Jin, X., & Mei, R. O. N. G. (2026) · Cells · doi:10.3390/cells15201859
“KLF4 has been proposed to respond to DNA methylation through conformational remodeling, potentially shifting between transcriptional activation and repression; it is also involved in regulating genes required for reproductive development [17,18].”
- Authors
- Liu, Y., Olanrewaju, Y. O., Zheng, Y., Hashimoto, H., Blumenthal, R. M., Zhang, X., & Cheng, X.
- Affiliations
- New England Biolabs (United States) (US)
- Corresponding author
- Cheng, X.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-02-11
- Volume
- 42
- Issue
- 8
- Pages
- 4859-4867
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC4005678
- OpenAlex
- W2037316977
- Cited by
- 99
- References
- 50
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 5 · 2022: 7 · 2021: 7 · 2020: 8 · 2019: 11 · 2018: 11 · 2017: 9 · 2016: 13 · 2015: 5 · 2014: 3
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nucleic Acids Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy
- Emory University
- Georgia Research Alliance
- University of Oxford
- National Institutes of Health
- Office of Science
- School of Medicine, Emory University
- National Institute of General Medical Sciences (R01GM049245, GM049245-20)
- Argonne National Laboratory
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- 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
- Keywords
- KLF4, DNA methylation, C2H2 zinc finger, DNA binding affinity, cellular reprogramming, epigenetic regulation, protein-DNA interactions
- MeSH terms
- Kruppel-Like Factor 4, Amino Acid Sequence, Animals, Arginine, Molecular Sequence Data, Protein Binding, Transcription Factors, Sequence Alignment, Glutamic Acid, CpG Islands, DNA Methylation, Mice, Kruppel-Like Transcription Factors
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