Histone deacetylase controls adult stem cell aging by balancing the expression of polycomb genes and jumonji domain containing 3

Abstract

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 p16INK4A regulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-009-0242-9) contains supplementary material, which is available to authorized users.

Epigenetic Modifications upon Senescence of Mesenchymal Stem Cells

“…H3K9ac and H3K14ac are required for the recruitment of different transcription factors [53] and the chromatin remodeling complex SWI/SNF, to initiate the transcription [54]. HDACs are generally downregulated upon senescence of MSCs, and this entails decreased expression of the polycomb group genes (PcGs) and an increased expression of Jumonji domain containing three (JMJD3) proteins, both involved in cell cycle control [55]. Thus, histone acetylation plays an important role for balancing genes involved in stemness as well as cell cycle progression.…”

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.…”

Genetics and Epigenetics of Aging and Longevity

“…Клеточное старение (перманентная остановка роста и деления клетки) сопровождается воз-никновением в ядре старение-ассоциированных участков гетерохроматина (SAHF), что обусловлено привлечени-ем гетерохроматиновых белков и белка Rb к промото-рам E2F-зависимых генов пролиферации, приводящим к репрессии генов-мишеней транскрипционного факто-ра E2F (Narita et al, 2003). При старении снижается ак-тивность метилтрансфераз DNMT1 и DNMT3a (Casillas et al, 2003), деацетилазы SIRT1 (Marton et al, 2010), увеличивается активность гистоновых деметилаз Jmjd3 (Jung et al, 2010) и Jarid1b (Nijwening et al, 2011), что приводит к неадаптивному изменению «эпигенетичес-кого ландшафта» клетки, изменению экспрессии генов, способствующему старению. Таким образом, анализ имеющихся сведений об эво-люционно-консервативной генетической регуляции ста-рения и долгожительства позволил сформировать фун-кциональную классификацию генов продолжительности жизни (Москалев, 2008) Carrano A. C., Liu Z., Dillin A.…”