DNA Methyltransferase Controls Stem Cell Aging by Regulating BMI1 and EZH2 through MicroRNAs

Abstract

Epigenetic regulation of gene expression is well known mechanism that regulates cellular senescence of cancer cells. Here we show that inhibition of DNA methyltransferases (DNMTs) with 5-azacytidine (5-AzaC) or with specific small interfering RNA (siRNA) against DNMT1 and 3b induced the cellular senescence of human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs) and increased p16INK4A and p21CIP1/WAF1 expression. DNMT inhibition changed histone marks into the active forms and decreased the methylation of CpG islands in the p16INK4A and p21CIP1/WAF1 promoter regions. Enrichment of EZH2, the key factor that methylates histone H3 lysine 9 and 27 residues, was decreased on the p16INK4A and p21CIP1/WAF1 promoter regions. We found that DNMT inhibition decreased expression levels of Polycomb-group (PcG) proteins and increased expression of microRNAs (miRNAs), which target PcG proteins. Decreased CpG island methylation and increased levels of active histone marks at genomic regions encoding miRNAs were observed after 5-AzaC treatment. Taken together, DNMTs have a critical role in regulating the cellular senescence of hUCB-MSCs through controlling not only the DNA methylation status but also active/inactive histone marks at genomic regions of PcG-targeting miRNAs and p16INK4A and p21CIP1/WAF1 promoter regions.

Cytotoxic and cytostatic side effects of chitosan nanoparticles as a non-viral gene carrier

“…The possibility that SIPS was caused by overexpression of the gene carried by CNs-pDNA and protein accumulation was excluded due to the fact that expressed fluorescent protein was characterized as non-toxic and biologically inert (Henderson and Remington, 2006). Furthermore, among many mechanisms engaged in senescence induction, also DNA and RNA methylation seems to play an important role (Machwe et al, 2000;Oh et al, 2015;So et al, 2011;Young and Smith, 2001). Besides that, DNA methyltransferase II (DNMT2), enzyme with the enigmatic role in the RNA methylation, was found to have protective role in the NPsinduced stress .…”

EZH2 mediates lidamycin-induced cellular senescence through regulating p21 expression in human colon cancer cells

“…36 Notably, EZH2 and DNA methyltransferases (DNMTs) are reported to be interacting with and regulated by each other to repress target genes expression including the CDK inhibitors. 37,38 Therefore, despite EZH2, there is possibility that DNMTs such as DNMT1 may also be affected by LDM. We indeed detected a reduction of DNMT1 protein expression by LDM (data not shown).…”

miR-543 and miR-590-3p regulate human mesenchymal stem cell aging via direct targeting of AIMP3/p18

“…Recently, we reported that the epigenetic regulators histone deacetylase (HDAC) and DNA methyltransferase (DNMT), as well as miRNAs, are important factors for maintaining stemness and for regulating cellular senescence in hMSCs (Jung et al 2010;Lee et al 2011;So et al 2011). Considering that HDAC and DNMT activities decrease in senescent cells, which corresponds with an increase in the expression of their target genes, we treated hMSCs with the HDAC inhibitors valproic acid (VPA) or sodium butyrate (SB) or with the DNMT inhibitor 5-azacytidine (5-azaC) and then examined the cells for changes in AIMP3/p18 expression.…”