Partial silencing of methyl cytosine protein binding 2 (MECP2) in mesenchymal stem cells induces senescence with an increase in damaged DNA.
DNA methylation is an epigenetic modification that occurs almost exclusively on CpG dinucleotides. MECP2 is a member of a family of proteins that preferentially bind to methylated CpGs. We analyzed the contribution of MECP2 to the physiology of mesenchymal stem cells (MSCs). Partial silencing of MECP2 in human MSCs induced a significant reduction of S-phase cells, along with an increase in G(1) cells. These changes were accompanied by a reduction of apoptosis, the triggering of senescence, a decrease in telomerase activity, and the down-regulation of genes involved in maintaining stem cell properties. Senescence appeared to rely on impairment of DNA damage repair and seemed to occur through RB- and P53-related pathways. The effects of MECP2 silencing could be related to the modification of the DNA methylation status. Our results indicate that the silencing of MECP2 induces an increase in methylated cytosines in the genome. Nevertheless, MECP2 partial silencing did not change the methylation of promoters, whose expression is affected by MECP2 down-regulation.
Squillaro
Tiziana
T
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, Pennsylvania, USA.
Alessio
Nicola
N
Cipollaro
Marilena
M
Renieri
Alessandra
A
Giordano
Antonio
A
Galderisi
Umberto
U
D002453:Cell Cycle / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D003596:Cytosine / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics; D015536:Down-Regulation; D020868:Gene Silencing; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D003596:Cytosine