A critique of the hypothesis that CA repeats are primary targets of neuronal MeCP2

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The DNA-binding protein MeCP2 is reported to bind methylated cytosine in CG and CA motifs in genomic DNA, but it was recently proposed that arrays of tandemly repeated CA containing either methylated or hydroxymethylated cytosine are the primary targets for MeCP2 binding and function. Here we investigated the predictions of this hypothesis using a range of published datasets. We failed to detect enrichment of cytosine modification at genomic CA repeat arrays in mouse brain regions and found no evidence for preferential MeCP2 binding at CA repeats. Moreover, we did not observe a correlation between the CA repeat density near genes and their degree of transcriptional deregulation when MeCP2 was absent. Our results do not provide support for the hypothesis that CA repeats are key mediators of MeCP2 function. Instead, we found that CA repeats are subject to CAC methylation to a degree that is typical of the surrounding genome and contribute modestly to MeCP2-mediated modulation of gene expression in accordance with their content of this canonical target motif.

Original languageEnglish
Article numbere202201522
Number of pages9
JournalLife Science Alliance
Issue number12
Early online date19 Sep 2022
Publication statusPublished - 1 Dec 2022


  • animals
  • metabolism
  • DNA methylation
  • DNA
  • methyl-CpG-binding protein 2
  • mice
  • neurons
  • cytosine


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