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Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA.

Liu K, Xu C, Lei M, Yang A, Loppnau P, Hughes TR, Min J
J Biol Chem 293 7344-7354 (2018)
Related entries: 6c1a, 6c1u, 6c1v, 6cnp, 6cnq

Cited: 31 times
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Abstract

Cytosine methylation is a well-characterized epigenetic mark and occurs at both CG and non-CG sites in DNA. Both methylated CG (mCG)- and mCH (H = A, C, or T)-containing DNAs, especially mCAC-containing DNAs, are recognized by methyl-CpG-binding protein 2 (MeCP2) to regulate gene expression in neuron development. However, the molecular mechanism involved in the binding of methyl-CpG-binding domain (MBD) of MeCP2 to these different DNA motifs is unclear. Here, we systematically characterized the DNA-binding selectivities of the MBD domains in MeCP2 and MBD1-4 with isothermal titration calorimetry-based binding assays, mutagenesis studies, and X-ray crystallography. We found that the MBD domains of MeCP2 and MBD1-4 bind mCG-containing DNAs independently of the sequence identity outside the mCG dinucleotide. Moreover, some MBD domains bound to both methylated and unmethylated CA dinucleotide-containing DNAs, with a preference for the CAC sequence motif. We also found that the MBD domains bind to mCA or nonmethylated CA DNA by recognizing the complementary TG dinucleotide, which is consistent with an overlooked ligand of MeCP2, i.e. the matrix/scaffold attachment regions (MARs/SARs) with a consensus sequence of 5'-GGTGT-3' that was identified in early 1990s. Our results also explain why MeCP2 exhibits similar binding affinity to both mCA- and hmCA-containing dsDNAs. In summary, our results suggest that in addition to mCG sites, unmethylated CA or TG sites also serve as DNA-binding sites for MeCP2 and other MBD-containing proteins. This discovery expands the genome-wide activity of MBD-containing proteins in gene regulation.

Articles - 6c1t mentioned but not cited (1)

  1. Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA. Liu K, Xu C, Lei M, Yang A, Loppnau P, Hughes TR, Min J. J Biol Chem 293 7344-7354 (2018)


Reviews citing this publication (7)

  1. Toward a Mechanistic Understanding of DNA Methylation Readout by Transcription Factors. Kribelbauer JF, Lu XJ, Rohs R, Mann RS, Bussemaker HJ. J Mol Biol 432 1801-1815 (2020)
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  6. Prospects for Use of Single-Cell Sequencing to Assess DNA Methylation in Asthma. Men S, Yu Y. Med Sci Monit 26 e925514 (2020)
  7. The NuRD Complex in Neurodevelopment and Disease: A Case of Sliding Doors. Boulasiki P, Tan XW, Spinelli M, Riccio A. Cells 12 1179 (2023)

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  1. Rational targeting of a NuRD subcomplex guided by comprehensive in situ mutagenesis. Sher F, Hossain M, Seruggia D, Schoonenberg VAC, Yao Q, Cifani P, Dassama LMK, Cole MA, Ren C, Vinjamur DS, Macias-Trevino C, Luk K, McGuckin C, Schupp PG, Canver MC, Kurita R, Nakamura Y, Fujiwara Y, Wolfe SA, Pinello L, Maeda T, Kentsis A, Orkin SH, Bauer DE. Nat Genet 51 1149-1159 (2019)
  2. Losing Dnmt3a dependent methylation in inhibitory neurons impairs neural function by a mechanism impacting Rett syndrome. Lavery LA, Ure K, Wan YW, Luo C, Trostle AJ, Wang W, Jin H, Lopez J, Lucero J, Durham MA, Castanon R, Nery JR, Liu Z, Goodell M, Ecker JR, Behrens MM, Zoghbi HY. Elife 9 e52981 (2020)
  3. The Nucleosome Remodeling and Deacetylase Complex Has an Asymmetric, Dynamic, and Modular Architecture. Low JKK, Silva APG, Sharifi Tabar M, Torrado M, Webb SR, Parker BL, Sana M, Smits C, Schmidberger JW, Brillault L, Jackman MJ, Williams DC, Blobel GA, Hake SB, Shepherd NE, Landsberg MJ, Mackay JP. Cell Rep 33 108450 (2020)
  4. MicroRNA-29 is an essential regulator of brain maturation through regulation of CH methylation. Swahari V, Nakamura A, Hollville E, Stroud H, Simon JM, Ptacek TS, Beck MV, Flowers C, Guo J, Plestant C, Liang J, Kurtz CL, Kanke M, Hammond SM, He YW, Anton ES, Sethupathy P, Moy SS, Greenberg ME, Deshmukh M. Cell Rep 35 108946 (2021)
  5. Neuronal non-CG methylation is an essential target for MeCP2 function. Tillotson R, Cholewa-Waclaw J, Chhatbar K, Connelly JC, Kirschner SA, Webb S, Koerner MV, Selfridge J, Kelly DA, De Sousa D, Brown K, Lyst MJ, Kriaucionis S, Bird A. Mol Cell 81 1260-1275.e12 (2021)
  6. Cytosine methylation of mitochondrial DNA at CpG sequences impacts transcription factor A DNA binding and transcription. Dostal V, Churchill MEA. Biochim Biophys Acta Gene Regul Mech 1862 598-607 (2019)
  7. Cytosine base modifications regulate DNA duplex stability and metabolism. Rausch C, Zhang P, Casas-Delucchi CS, Daiß JL, Engel C, Coster G, Hastert FD, Weber P, Cardoso MC. Nucleic Acids Res 49 12870-12894 (2021)
  8. Cathelicidin antimicrobial peptide (CAMP) gene promoter methylation induces chondrocyte apoptosis. Wang G, Li Y, Yang G, Yang T, He L, Wang Y. Hum Genomics 15 24 (2021)
  9. Densely methylated DNA traps Methyl-CpG-binding domain protein 2 but permits free diffusion by Methyl-CpG-binding domain protein 3. Leighton GO, Irvin EM, Kaur P, Liu M, You C, Bhattaram D, Piehler J, Riehn R, Wang H, Pan H, Williams DC. J Biol Chem 298 102428 (2022)
  10. The C-terminal D/E-rich domain of MBD3 is a putative Z-DNA mimic that competes for Zα DNA-binding activity. Lee CH, Shih YP, Ho MR, Wang AH. Nucleic Acids Res 46 11806-11821 (2018)
  11. Structural Insights into Methylated DNA Recognition by the Methyl-CpG Binding Domain of MBD6 from Arabidopsis thaliana. Mahana Y, Ohki I, Walinda E, Morimoto D, Sugase K, Shirakawa M. ACS Omega 7 3212-3221 (2022)
  12. Silencing of MBD2 and EZH2 inhibits the proliferation of colorectal carcinoma cells by rescuing the expression of SFRP. Xie Y, Wang F, Yu J, Zhang J, Liu Y, Li M, Qi J. Oncol Rep 46 250 (2021)
  13. Structural basis of the TAM domain of BAZ2A in binding to DNA or RNA independent of methylation status. Chen S, Zhou M, Dong A, Loppnau P, Wang M, Min J, Liu K. J Biol Chem 297 101351 (2021)
  14. DNA methyltransferase DNMT3A forms interaction networks with the CpG site and flanking sequence elements for efficient methylation. Dukatz M, Dittrich M, Stahl E, Adam S, de Mendoza A, Bashtrykov P, Jeltsch A. J Biol Chem 298 102462 (2022)
  15. The MECP2-TRD domain interacts with the DNMT3A-ADD domain at the H3-tail binding site. Kunert S, Linhard V, Weirich S, Choudalakis M, Osswald F, Krämer L, Köhler AR, Bröhm A, Wollenhaupt J, Schwalbe H, Jeltsch A. Protein Sci 32 e4542 (2023)
  16. Crystal structure of the BAZ2B TAM domain. Feng Y, Chen S, Zhou M, Zhang J, Min J, Liu K. Heliyon 8 e09873 (2022)
  17. Genome-wide identification of MBD gene family members in Eleutherococcus senticosus with their expression motifs under drought stress and DNA demethylation. Wang S, Dong J, Zhao XL, Song X, Long YH, Xing ZB. BMC Genomics 24 84 (2023)
  18. A genome-wide analysis reveals the MeCP2-dependent regulation of genes in BGC-823 cells. Liu YX, Li LY, Diao ZJ, He YM, Chen Y, Hou N, Zhao LY, Huang C. Int J Clin Exp Pathol 13 1578-1589 (2020)
  19. Computational discovery of novel inhibitory candidates targeting versatile transcriptional repressor MBD2. Çalışkaner ZO. J Mol Model 28 296 (2022)
  20. Molecular mechanism of specific DNA sequence recognition by NRF1. Liu K, Li W, Xiao Y, Lei M, Zhang M, Min J. Nucleic Acids Res 52 953-966 (2024)
  21. Proteins That Read DNA Methylation. Liu K, Shimbo T, Song X, Wade PA, Min J. Adv Exp Med Biol 1389 269-293 (2022)
  22. Variable predicted pathogenic mechanisms for novel MECP2 variants in RTT patients. Sharaf-Eldin WE, Issa MY, Zaki MS, Kilany A, Fayez AG. J Genet Eng Biotechnol 20 44 (2022)
  23. Variant Profile of MECP2 Gene in Sri Lankan Patients with Rett Syndrome. Hettiarachchi D, Neththikumara NF, Pathirana BAPS, Dissanayake VHW. J Autism Dev Disord 50 118-126 (2020)


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