MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2

Epigenetics Chromatin. 2019 Oct 10;12(1):63. doi: 10.1186/s13072-019-0298-1.


Background: MeCP2-a chromatin-binding protein associated with Rett syndrome-has two main isoforms, MeCP2-E1 and MeCP2-E2, differing in a few N-terminal amino acid residues. Previous studies have shown brain region-specific expression of these isoforms which, in addition to their different cellular localization and differential expression during brain development, suggest that they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored.

Results: Here, we show that the N-terminal domains (NTD) of MeCP2-E1 and E2 modulate the ability of the methyl-binding domain (MBD) to interact with DNA as well as influencing the turn-over rates, binding dynamics, response to neuronal depolarization, and circadian oscillations of the two isoforms. Our proteomics data indicate that both isoforms exhibit unique interacting protein partners. Moreover, genome-wide analysis using ChIP-seq provide evidence for a shared as well as a specific regulation of different sets of genes.

Conclusions: Our study supports the idea that Rett syndrome might arise from simultaneous impairment of cellular processes involving non-overlapping functions of MECP2 isoforms. For instance, MeCP2-E1 mutations might impact stimuli-dependent chromatin regulation, while MeCP2-E2 mutations could result in aberrant ribosomal expression. Overall, our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.

Keywords: Chromatin; Isoforms; MeCP2; Rett syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chromatin / metabolism
  • Circadian Rhythm / genetics
  • DNA / metabolism*
  • Humans
  • Methyl-CpG-Binding Protein 2 / chemistry
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / metabolism*
  • Mice
  • Mice, Knockout
  • Neurons / metabolism
  • Protein Binding
  • Protein Domains
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Rett Syndrome / genetics
  • Rett Syndrome / pathology


  • Chromatin
  • Methyl-CpG-Binding Protein 2
  • Protein Isoforms
  • DNA