MeCP2 deficiency downregulates specific nuclear proteins that could be partially recovered by valproic acid in vitro

Manuela Vecsler, Amos J. Simon, Ninette Amariglio, Gideon Rechavi, Eva Gak

Research output: Contribution to journalArticlepeer-review

Abstract

MeCP2, the major causative factor of Rett syndrome and related phenotypes including autism, is a two-face nuclear modulator acting via transcriptional and chromatin remodeling mechanisms. This study investigated the expression of several nuclear proteins and their dependence on MeCP2 dose and presence of the Rett causative R306C mutation. To this end, we developed in vitro models representing MeCP2 deficiency induced by siRNAs, and cells expressing the R306C mutation. Using an extended antibody microarray validated by specific assays, revealed that MeCP2 dose was correlated with specific nuclear proteins profiles including the BRM/SNF2 component of SWI/SNF complex, PRMT1 methyl transferase and HDAC2. Furthermore, while exposing the MeCP2 knock-down system to therapeutic concentrations of valproic acid (VPA), a known HDACs inhibitor, we observed a partial restoration of MeCP2 expression levels. Exposure to VPA also increased the levels of BRM, as well as of BDNF, an important co-factor in MeCP2-mediated pathway. Our findings provide additional evidence of diverse mechanisms of MeCP2 function as transcriptional repressor and activator of specific genes. as it has been recently demonstrated that post-natal restoration of MeCP2 deficiency may reverse neurological defects in a mouse model of Rett syndrome, we suggest to study the restorative effect of HDAC inhibitors in MeCP2-deficient mouse model.

Original languageEnglish
Pages (from-to)61-67
Number of pages7
JournalEpigenetics
Volume5
Issue number1
DOIs
StatePublished - 1 Jan 2010
Externally publishedYes

Keywords

  • Chromatin remodeling
  • Gene expression
  • HDAC inhibitors
  • Methyl CpG binding protein 2 (MeCP2)
  • Rett syndrome

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