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Lee, Seunghee,Jung, Ji-Won,Park, Sang-Bum,Roh, Kyounghwan,Lee, Su Yeon,Kim, Ju Han,Kang, Soo-Kyung,Kang, Kyung-Sun SP Birkhäuser Verlag Basel 2011 Cellular and molecular life sciences Vol.68 No.2
<P>Cellular senescence involves a reduction in adult stem cell self-renewal, and epigenetic regulation of gene expression is one of the main underlying mechanisms. Here, we observed that the cellular senescence of human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs) caused by inhibition of histone deacetylase (HDAC) activity leads to down-regulation of high mobility group A2 (HMGA2) and, on the contrary, to up-regulation of p16<SUP>INK4A</SUP>, p21<SUP>CIP1/WAF1</SUP> and p27<SUP>KIP1</SUP>. We found that let-7a1, let-7d, let-7f1, miR-23a, miR-26a and miR-30a were increased during replicative and HDAC inhibitor-mediated senescence of hUCB-MSCs by microRNA microarray and real-time quantitative PCR. Furthermore, the configurations of chromatins beading on these miRNAs were prone to transcriptional activation during HDAC inhibitor-mediated senescence. We confirmed that miR-23a, miR-26a and miR-30a inhibit HMGA2 to accelerate the progress of senescence. These findings suggest that HDACs may play important roles in cellular senescence by regulating the expression of miRNAs that target HMGA2 through histone modification.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1007/s00018-010-0457-9) contains supplementary material, which is available to authorized users.</P>
Jung, Ji-Won,Lee, Seunghee,Seo, Min-Soo,Park, Sang-Bum,Kurtz, Andreas,Kang, Soo-Kyung,Kang, Kyung-Sun SP Birkhäuser Verlag Basel 2010 Cellular and molecular life sciences Vol.67 No.7
<P>Aging is linked to loss of the self-renewal capacity of adult stem cells. Here, we observed that human multipotent stem cells (MSCs) underwent cellular senescence in vitro. Decreased expression of histone deacetylases (HDACs), followed by downregulation of polycomb group genes (PcGs), such as BMI1, EZH2 and SUZ12, and by upregulation of jumonji domain containing 3 (JMJD3), was observed in senescent MSCs. Similarly, HDAC inhibitors induced cellular senescence through downregulation of PcGs and upregulation of JMJD3. Regulation of PcGs was associated with HDAC inhibitor-induced hypophosphorylation of RB, which causes RB to bind to and decrease the transcriptional activity of E2F. JMJD3 expression regulation was dependant on histone acetylation status at its promoter regions. A histone acetyltransferase (HAT) inhibitor prevented replicative senescence of MSCs. These results suggest that HDAC activity might be important for MSC self-renewal by balancing PcGs and JMJD3 expression, which govern cellular senescence by p16<SUP>INK4A</SUP> regulation.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1007/s00018-009-0242-9) contains supplementary material, which is available to authorized users.</P>