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Unraveling the Mechanism of Epigenetic Control of Transcription

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— 1 min read

Recent research published in the journal Biochemistry has shed light on the selective recognition of methylated CpG dinucleotides by methylation-sensitive sequence-specific DNA binding proteins. The study, conducted by V.V. Lao and colleagues from Loma Linda University, Department of Basic Sciences, probed the mechanism of selective interaction of the methyl-binding protein with methylated DNA. The researchers prepared a series of oligonucleotides containing modified purines and pyrimidines at the recognition site and examined their binding to the methyl-binding domain (MBD) of the methyl-CpG-binding protein 2 (MeCP2).

Key Takeaways:

  • The study found that pyrimidine 5-substituents similar in size to a methyl group facilitate protein binding, but binding affinity does not correlate with the hydrophobicity of the substituent.
  • The 4-amino group of 5-methylcytosine (mC) and Watson-Crick base pair geometry are not essential for MBD binding.
  • The guanine O6 and N7 atoms present in the major groove are crucial for recognition.
  • Removal of the guanine 2-amino group from the minor groove enhances MBD binding, likely due to DNA bending at the substitution site.
  • The enhanced binding of the MBD to oligonucleotides containing several cytosine analogues is better explained by a DNA-protein interface mediated by structured water as opposed to hydrophobic interactions.
  • The study has implications for understanding the epigenetic control of transcription and the recognition of methylated DNA by methylation-sensitive sequence-specific DNA binding proteins.

Statistics:

  • 5-substituted uracil analogues in one strand do not direct human DNA methyltransferase 1 (DNMT1) methylation of the opposing strand, as does mC.
  • The study observed enhanced binding of the MBD to oligonucleotides containing several cytosine analogues.
  • The binding of these oligonucleotides to the MBD of MeCP2 was examined using a series of oligonucleotides containing modified purines and pyrimidines.
  • The study was published in Biochemistry (Impact of base analogues within a CpG dinucleotide on the binding of DNA by the methyl-binding domain of MeCP2 and methylation by DNMT1. Biochemistry, 2010;49(47):10228-36).

Sources:

  • Lao, V.V., et al. "Impact of base analogues within a CpG dinucleotide on the binding of DNA by the methyl-binding domain of MeCP2 and methylation by DNMT1." Biochemistry, 2010;49(47):10228-36.
  • Loma Linda University, Department of Basic Sciences.
  • Science Letter editors. "Unraveling the Mechanism of Epigenetic Control of Transcription." Science Letter, 2011.

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