MeCP2 deficiency downregulates specific nuclear proteins that could be partially recovered by valproic acid in vitro.
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.
Vecsler
Manuela
M
Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel.
Simon
Amos J
AJ
Amariglio
Ninette
N
Rechavi
Gideon
G
Gak
Eva
E
D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D066298:In Vitro Techniques; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000378:metabolism; D015518:Rett Syndrome / Q000378:metabolism; D014158:Transcription, Genetic; D014635:Valproic Acid / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D051783:Methyl-CpG-Binding Protein 2; D034741:RNA, Small Interfering; D014635:Valproic Acid