Epigenetic Regulation of Bone Marrow Stem Cell Aging: Revealing Epigenetic Signatures associated with Hematopoietic and Mesenchymal Stem Cell Aging
Dimitrios Cakouros1,2, Stan Gronthos1,2,*
1Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia. 2South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
In this review we explore the importance of epigenetics as a contributing factor for aging adult stem cells. We summarize the latest findings of epigenetic factors deregulated as adult stem cells age and the consequence on stem cell self-renewal and differentiation, with a focus on adult stem cells in the bone marrow. With the latest whole genome bisulphite sequencing and chromatin immunoprecipitations we are able to decipher an emerging pattern common for adult stem cells in the bone marrow niche and how this might correlate to epigenetic enzymes deregulated during aging. We begin by briefly discussing the initial observations in yeast, drosophila and Caenorhabditis elegans (C. elegans) that led to the breakthrough research that identified the role of epigenetic changes associated with lifespan and aging. We then focus on adult stem cells, specifically in the bone marrow, which lends strong support for the deregulation of DNA methyltransferases, histone deacetylases, acetylates, methyltransferases and demethylases in aging stem cells, and how their corresponding epigenetic modifications influence gene expression and the aging phenotype. Given the reversible nature of epigenetic modifications we envisage “epi” targeted therapy as a means to reprogram aged stem cells into their younger counterparts.
Figure 1. Age Associated Epigenetic Changes in Organisms. Histone and DNA modification marks associated with aging in different species is shown as well as their associated epigenetic enzymes. The effect on aging and lifespan is also shown.
Figure 2. Age Associated Epigenetic Changes in Aged HSC/MSC. Histone and DNA modification marks in aged HSC and MSC are shown as well as their associated epigenetic enzymes. The effect on HSC/MSC aging is shown.
Figure 3. Chromatin Structure of Stemness and differentiation genes in Aged HSC/MSC. Histone and DNA modification marks in aged HSC and MSC consist of DNA methylation, H3K9me3 and H3K27me3 being more abundant along lineage/differentiation promoters therefore inhibiting transcription and differentiation. This is more apparent on lymphoid genes in HSC therefore skewing differentiation towards the myeloid lineage. Stemness genes contain an abundance of active marks such as H3K4me1, H3K4me3 and H3K27Ac leading to an open chromatin conformation and keeping the adult stem cells in an immature state.
Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, et al. (2007). Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature, 448:553-560.
Bernstein BE, Meissner A, Lander ES (2007). The mammalian epigenome. Cell, 128:12.
Gifford CA, Ziller MJ, Gu H, Trapnell C, Donaghey J, Tsankov A, et al. (2013). Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell, 153:1149-1163.
Orford K, Kharchenko P, Lai W, Dao MC, Worhunsky DJ, Ferro A, et al. (2008). Differential H3K4 methylation identifies developmentally poised hematopoietic genes. Dev Cell, 14:798-809.
Park SH, Park SH, Kook MC, Kim EY, Park S, Lim JH (2004). Ultrastructure of human embryonic stem cells and spontaneous and retinoic acid-induced differentiating cells. Ultrastruct Pathol, 28:229-238.
Efroni S, Duttagupta R, Cheng J, Dehghani H, Hoeppner DJ, Dash C, et al. (2008). Global transcription in pluripotent embryonic stem cells. Cell Stem Cell, 2:437-447.
Golebiewska A, Atkinson SP, Lako M, Armstrong L (2009). Epigenetic landscaping during hESC differentiation to neural cells. Stem Cells, 27:1298-1308.
Wen B, Wu H, Shinkai Y, Irizarry RA, Feinberg AP (2009). Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nat Genet, 41:246-250.
Juan AH, Wang S, Ko KD, Zare H, Tsai PF, Feng X, et al. (2016). Roles of H3K27me2 and H3K27me3 Examined during Fate Specification of Embryonic Stem Cells. Cell Rep, 17:1369-1382.
Chen T, Dent SY (2014). Chromatin modifiers and remodellers: regulators of cellular differentiation. Nat Rev Genet, 15:93-106.
Kim S, Villeponteau B, Jazwinski SM (1996). Effect of replicative age on transcriptional silencing near telomeres in Saccharomyces cerevisiae. Biochem Biophys Res Commun, 219:370-376.
Smeal T, Claus J, Kennedy B, Cole F, Guarente L (1996). Loss of transcriptional silencing causes sterility in old mother cells of S. cerevisiae. Cell, 84:633-642.
Feser J, Truong D, Das C, Carson JJ, Kieft J, Harkness T, et al. (2010). Elevated histone expression promotes life span extension. Mol Cell, 39:724-735.
Feser J, Tyler J (2011). Chromatin structure as a mediator of aging. FEBS Lett, 585:2041-2048.
O’Sullivan RJ, Karlseder J (2012). The great unravelling: chromatin as a modulator of the aging process. Trends Biochem Sci, 37:466-476.
Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, et al. (2003). Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell, 113:703-716.
Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, et al. (2005). Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell, 8:19-30.
Kosar M, Bartkova J, Hubackova S, Hodny Z, Lukas J, Bartek J (2011). Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a). Cell Cycle, 10:457-468.
Chandra T, Kirschner K, Thuret JY, Pope BD, Ryba T, Newman S, et al. (2012). Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation. Mol Cell, 47:203-214.
Harr JC, Luperchio TR, Wong X, Cohen E, Wheelan SJ, Reddy KL (2015). Directed targeting of chromatin to the nuclear lamina is mediated by chromatin state and A-type lamins. J Cell Biol, 208:33-52.
Shah PP, Donahue G, Otte GL, Capell BC, Nelson DM, Cao K, et al. (2013). Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev, 27:1787-1799.
Kaeberlein M, McVey M, Guarente L (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev, 13:2570-2580.
Frye RA (1999). Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun, 260:273-279.
Villeponteau B (1997). The heterochromatin loss model of aging. Exp Gerontol, 32:383-394.
Landry J, Sutton A, Tafrov ST, Heller RC, Stebbins J, Pillus L, et al. (2000). The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc Natl Acad Sci U S A, 97:5807-5811.
Tsurumi A, Li WX (2012). Global heterochromatin loss: a unifying theory of aging? Epigenetics, 7:680-688.
Dang W, Steffen KK, Perry R, Dorsey JA, Johnson FB, Shilatifard A, et al. (2009). Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature, 459:802-807.
Wood JG, Hillenmeyer S, Lawrence C, Chang C, Hosier S, Lightfoot W, et al. (2010). Chromatin remodeling in the aging genome of Drosophila. Aging Cell, 9:971-978.
Larson K, Yan SJ, Tsurumi A, Liu J, Zhou J, Gaur K, et al. (2012). Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet, 8:e1002473.
Siebold AP, Banerjee R, Tie F, Kiss DL, Moskowitz J, Harte PJ (2010). Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance. Proc Natl Acad Sci U S A, 107:169-174.
Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, et al. (2010). Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature, 466:383-387.
Jin C, Li J, Green CD, Yu X, Tang X, Han D, et al. (2011). Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway. Cell Metab, 14:161-172.
Maures TJ, Greer EL, Hauswirth AG, Brunet A (2011). The H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent manner. Aging Cell, 10:980-990.
Rogina B, Helfand SL (2004). Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A, 101:15998-16003.
Tissenbaum HA, Guarente L (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410:227-230.
Ford E, Voit R, Liszt G, Magin C, Grummt I, Guarente L (2006). Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev, 20:1075-1080.
Li C, Mueller JE, Bryk M (2006). Sir2 represses endogenous polymerase II transcription units in the ribosomal DNA nontranscribed spacer. Mol Biol Cell, 17:3848-3859.
Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, Patel P, et al. (2003). Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A, 100:10794-10799.
McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, et al. (2003). The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol, 23:38-54.
Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, et al. (2008). Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell, 14:312-323.
Bao J, Sack MN (2010). Protein deacetylation by sirtuins: delineating a post-translational regulatory program responsive to nutrient and redox stressors. Cell Mol Life Sci, 67:3073-3087.
Satoh A, Brace CS, Rensing N, Cliften P, Wozniak DF, Herzog ED, et al. (2013). Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab, 18:416-430.
Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, et al. (2008). SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature, 452:492-496.
Yang B, Zwaans BM, Eckersdorff M, Lombard DB (2009). The sirtuin SIRT6 deacetylates H3 K56Ac in vivo to promote genomic stability. Cell Cycle, 8:2662-2663.
Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, et al. (2010). Altered histone acetylation is associated with age-dependent memory impairment in mice. Science, 328:753-756.
Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, et al. (2010). Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology, 35:870-880.
Edwards C, Canfield J, Copes N, Rehan M, Lipps D, Bradshaw PC (2014). D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging (Albany NY), 6:621-644.
Shumaker DK, Dechat T, Kohlmaier A, Adam SA, Bozovsky MR, Erdos MR, et al. (2006). Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci U S A, 103:8703-8708.
Liu B, Yip R, Zhou Z (2012). Chromatin remodeling, DNA damage repair and aging. Curr Genomics, 13:533-547.
Columbaro M, Capanni C, Mattioli E, Novelli G, Parnaik VK, Squarzoni S, et al. (2005). Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment. Cell Mol Life Sci, 62:2669-2678.
Krishnan V, Chow MZ, Wang Z, Zhang L, Liu B, Liu X, et al. (2011). Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proc Natl Acad Sci U S A, 108:12325-12330.
Geiger H, de Haan G, Florian MC (2013). The ageing haematopoietic stem cell compartment. Nat Rev Immunol, 13:376-389.
Wahlestedt M, Pronk CJ, Bryder D (2015). Concise review: hematopoietic stem cell aging and the prospects for rejuvenation. Stem Cells Transl Med, 4:186-194.
Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA (2007). Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol, 5:e201.
Sun D, Luo M, Jeong M, Rodriguez B, Xia Z, Hannah R, et al. (2014). Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell, 14:673-688.
Issa JP (2014). Aging and epigenetic drift: a vicious cycle. J Clin Invest, 124:24-29.
Warren LA, Rossi DJ (2009). Stem cells and aging in the hematopoietic system. Mech Ageing Dev, 130:46-53.
Beerman I, Bhattacharya D, Zandi S, Sigvardsson M, Weissman IL, Bryder D, et al. (2010). Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A, 107:5465-5470.
Muller-Sieburg CE, Sieburg HB, Bernitz JM, Cattarossi G (2012). Stem cell heterogeneity: implications for aging and regenerative medicine. Blood, 119:3900-3907.
Challen GA, Boles NC, Chambers SM, Goodell MA (2010). Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell, 6:265-278.
Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, et al. (2006). Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med, 12:446-451.
Laird PW (2010). Principles and challenges of genomewide DNA methylation analysis. Nat Rev Genet, 11:191-203.
Lovkvist C, Dodd IB, Sneppen K, Haerter JO (2016). DNA methylation in human epigenomes depends on local topology of CpG sites. Nucleic Acids Res.
Gonzalo S (2010). Epigenetic alterations in aging. J Appl Physiol (1985), 109:586-597.
Fuke C, Shimabukuro M, Petronis A, Sugimoto J, Oda T, Miura K, et al. (2004). Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study. Ann Hum Genet, 68:196-204.
McClay JL, Aberg KA, Clark SL, Nerella S, Kumar G, Xie LY, et al. (2014). A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects. Hum Mol Genet, 23:1175-1185.
Broske AM, Vockentanz L, Kharazi S, Huska MR, Mancini E, Scheller M, et al. (2009). DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet, 41:1207-1215.
Trowbridge JJ, Snow JW, Kim J, Orkin SH (2009). DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell, 5:442-449.
Tadokoro Y, Ema H, Okano M, Li E, Nakauchi H (2007). De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J Exp Med, 204:715-722.
Challen GA, Sun D, Mayle A, Jeong M, Luo M, Rodriguez B, et al. (2014). Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells. Cell Stem Cell, 15:350-364.
Pastor WA, Pape UJ, Huang Y, Henderson HR, Lister R, Ko M, et al. (2011). Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature, 473:394-397.
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. (2009). Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science, 324:930-935.
Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, et al. (2011). Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell, 8:200-213.
Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, et al. (2011). Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci U S A, 108:14566-14571.
Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, et al. (2011). Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood, 118:4509-4518.
Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. (2011). Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell, 20:11-24.
Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. (2014). Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med, 20:1472-1478.
Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. (2014). Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med, 371:2477-2487.
Buscarlet M, Tessier A, Provost S, Mollica L, Busque L (2016). Human blood cell levels of 5-hydroxymethylcytosine (5hmC) decline with age, partly related to acquired mutations in TET2. Exp Hematol, 44:1072-1084.
Passegue E, Wagers AJ, Giuriato S, Anderson WC, Weissman IL (2005). Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med, 202:1599-1611.
Sudo K, Ema H, Morita Y, Nakauchi H (2000). Age-associated characteristics of murine hematopoietic stem cells. J Exp Med, 192:1273-1280.
Nygren JM, Bryder D, Jacobsen SE (2006). Prolonged cell cycle transit is a defining and developmentally conserved hemopoietic stem cell property. J Immunol, 177:201-208.
Beerman I, Bock C, Garrison BS, Smith ZD, Gu H, Meissner A, et al. (2013). Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell, 12:413-425.
Taiwo O, Wilson GA, Emmett W, Morris T, Bonnet D, Schuster E, et al. (2013). DNA methylation analysis of murine hematopoietic side population cells during aging. Epigenetics, 8:1114-1122.
Steegenga WT, Boekschoten MV, Lute C, Hooiveld GJ, de Groot PJ, Morris TJ, et al. (2014). Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs. Age (Dordr), 36:9648.
Sierra MI, Fernandez AF, Fraga MF (2015). Epigenetics of Aging. Curr Genomics, 16:435-440.
Campion J, Milagro FI, Martinez JA (2009). Individuality and epigenetics in obesity. Obes Rev, 10:383-392.
Almen MS, Nilsson EK, Jacobsson JA, Kalnina I, Klovins J, Fredriksson R, et al. (2014). Genome-wide analysis reveals DNA methylation markers that vary with both age and obesity. Gene, 548:61-67.
Chouliaras L, van den Hove DL, Kenis G, Keitel S, Hof PR, van Os J, et al. (2012). Age-related increase in levels of 5-hydroxymethylcytosine in mouse hippocampus is prevented by caloric restriction. Curr Alzheimer Res, 9:536-544.
Chouliaras L, van den Hove DL, Kenis G, Dela Cruz J, Lemmens MA, van Os J, et al. (2011). Caloric restriction attenuates age-related changes of DNA methyltransferase 3a in mouse hippocampus. Brain Behav Immun, 25:616-623.
Herzog M, Josseaux E, Dedeurwaerder S, Calonne E, Volkmar M, Fuks F (2012). The histone demethylase Kdm3a is essential to progression through differentiation. Nucleic Acids Res, 40:7219-7232.
Kidder BL, Hu G, Zhao K (2014). KDM5B focuses H3K4 methylation near promoters and enhancers during embryonic stem cell self-renewal and differentiation. Genome Biol, 15:R32.
Stalker L, Wynder C (2012). Evaluation of histone-modifying enzymes in stem cell populations. Methods Mol Biol, 809:411-426.
Thieme S, Gyárfás T, Richter C, Özhan G, Fu J, Alexopoulou D, et al. (2013). The histone demethylase UTX regulates stem cell migration and hematopoiesis. Blood, 121:13.
Cellot S, Hope KJ, Chagraoui J, Sauvageau M, Deneault E, MacRae T, et al. (2013). RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity. Blood, 122:1545-1555.
Shih AH, Abdel-Wahab O, Patel JP, Levine RL (2012). The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer, 12:599-612.
Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC, Majeti R (2014). Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci U S A, 111:2548-2553.
Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR, et al. (2012). Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med, 4:149ra118.
Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, et al. (2014). Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature, 506:328-333.
Kamminga LM, Bystrykh LV, de Boer A, Houwer S, Douma J, Weersing E, et al. (2005). The polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood, 107:2170-2179.
Konuma T, Oguro H, Iwama A (2010). Role of the polycomb group proteins in hematopoietic stem cells. Dev Growth Differ, 52:505-516.
Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, et al. (2003). Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature, 423:302-305.
Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, Tsukui H, et al. (2004). Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity, 21:843-851.
Oguro H, Iwama A, Morita Y, Kamijo T, van Lohuizen M, Nakauchi H (2006). Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J Exp Med, 203:2247-2253.
Hidalgo I, Herrera-Merchan A, Ligos JM, Carramolino L, Nunez J, Martinez F, et al. (2012). Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest. Cell Stem Cell, 11:649-662.
Xie R, Everett LJ, Lim HW, Patel NA, Schug J, Kroon E, et al. (2013). Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell, 12:224-237.
Singh SK, Williams CA, Klarmann K, Burkett SS, Keller JR, Oberdoerffer P (2013). Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance. J Exp Med, 210:987-1001.
Brown K, Xie S, Qiu X, Mohrin M, Shin J, Liu Y, et al. (2013). SIRT3 reverses aging-associated degeneration. Cell Rep, 3:319-327.
Kamminga LM, Bystrykh LV, de Boer A, Houwer S, Douma J, Weersing E, et al. (2006). The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood, 107:2170-2179.
Friedenstein A, Chailakhyan R, Lalykina K (1970). The development of fibroblast colonies in monolayer cultures of guinea pig bone marrow and spleen cells. Cell Tissue Kinet, 3:393.
Castro-Malaspina H, Gay RE, Resnick G, Kapoor N, Meyers P, Chiarieri D, et al. (1980). Characterization of human bone marrow fibroblast colony-forming cells (CFU-F) and their progeny. Blood, 56:289-301.
Owen M, Friedenstein A (1988). Marrow-derived osteogenic precursors. CIba Found Symp, 136:42-60.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284:143-147.
Gronthos S, Zannettino A, hay S, Shi S, Graves S, Kortesidis A, et al. (2003). Molecular and Cellular characterisation of highly purified stromal cells derived from human bone marrow. J Cell Sci, 116:1827-1835.
Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, et al. (2007). Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell, 131:324-336.
Shi S, Gronthos S, Chen S, Reddi A, Counter CM, Robey PG, et al. (2002). Bone formation by human postnatal bone marrow stromal stem cells is enhanced by telomerase expression. Nat Biotechnol, 20:587-591.
Simonsen JL, Rosada C, Serakinci N, Justesen J, Stenderup K, Rattan SI, et al. (2002). Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat Biotechnol, 20:592-596.
Gronthos S, Brahim J, Li W, Fisher LW, Cherman N, Boyde A, et al. (2002). Stem cell properties of human dental pulp stem cells. J Dent Res, 81:531-535.
Menicanin D, Bartold MP, W ZAC, Gronthos S (2010). Identification of a common gene Expression Signature Associated with Immature Clonal Mesenchymal Cell Populations Derived from Bone Marrow and Dental Tissues. Stem Cells and Development, 19:1501-1510.
Baxter MA, Wynn RF, Jowitt SN, Wraith JE, Fairbairn LJ, Bellantuono I (2004). Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells, 22:675-682.
Stolzing A, Jones E, McGonagle D, Scutt A (2008). Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev, 129:163-173.
D’Ippolito G, Schiller PC, Ricordi C, Roos BA, Howard GA (1999). Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow. J Bone Miner Res, 14:1115-1122.
Tsai CC, Hung SC (2012). Functional roles of pluripotency transcription factors in mesenchymal stem cells. Cell Cycle, 11:3711-3712.
Li Z, Liu C, Xie Z, Song P, Zhao RC, Guo L, et al. (2011). Epigenetic dysregulation in mesenchymal stem cell aging and spontaneous differentiation. PLoS One, 6:e20526.
So AY, Jung JW, Lee S, Kim HS, Kang KS (2011). DNA methyltransferase controls stem cell aging by regulating BMI1 and EZH2 through microRNAs. PLoS One, 6:e19503.
Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, et al. (2007). The polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes and Development, 21:525-530.
Cakouros D, Isenmann S, Cooper L, Zannettino A, Anderson P, Glackin C, et al. (2012). Twist-1 induces Ezh2 recruitment regulating histone methylation along the Ink4A/Arf locus in mesenchymal stem cells. Mol Cell Biol, 32:8.
Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y (2007). pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene. Genes Dev, 21:49-54.
Cui H, Hu B, Li T, Ma J, Alam G, Gunning WT, et al. (2007). Bmi-1 is essential for the tumorigenicity of neuroblastoma cells. Am J Pathol, 170:1370-1378.
Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M (1999). The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature, 397:164-168.
Wang H, Pan K, Zhang HK, Weng DS, Zhou J, Li JJ, et al. (2008). Increased polycomb-group oncogene Bmi-1 expression correlates with poor prognosis in hepatocellular carcinoma. J Cancer Res Clin Oncol, 134:535-541.
Isenmann S, Arthur A, Zannettino A, Turner J, Shi S, Glackin C, et al. (2009). Twist family of basic-helix-loop-helix transcription factors mediate human mesenchymal stem cell growth and commitment. Stem Cells, 27:2457-2468.
Bork S, Pfister S, Witt H, Horn P, Korn B, Ho AD, et al. (2010). DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells. Aging Cell, 9:54-63.
Fernandez AF, Bayon GF, Urdinguio RG, Torano EG, Garcia MG, Carella A, et al. (2015). H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells. Genome Res, 25:27-40.
Rakyan VK, Down TA, Maslau S, Andrew T, Yang TP, Beyan H, et al. (2010). Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res, 20:434-439.
Horvath S, Zhang Y, Langfelder P, Kahn RS, Boks MP, van Eijk K, et al. (2012). Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol, 13:R97.
Liu L, van Groen T, Kadish I, Li Y, Wang D, James SR, et al. (2011). Insufficient DNA methylation affects healthy aging and promotes age-related health problems. Clin Epigenetics, 2:349-360.
Torano EG, Bayon GF, Del Real A, Sierra MI, Garcia MG, Carella A, et al. (2016). Age-associated hydroxymethylation in human bone-marrow mesenchymal stem cells. J Transl Med, 14:207.
Kudlow BA, Kennedy BK, Monnat RJ Jr. (2007). Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol, 8:394-404.
Muftuoglu M, Oshima J, von Kobbe C, Cheng WH, Leistritz DF, Bohr VA (2008). The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis. Hum Genet, 124:369-377.
Goto M, Ishikawa Y, Sugimoto M, Furuichi Y (2013). Werner syndrome: a changing pattern of clinical manifestations in Japan (1917~2008). Biosci Trends, 7:13-22.
Zhang W, Li J, Suzuki K, Qu J, Wang P, Zhou J, et al. (2015). Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science, 348:1160-1163.
Jung JW, Lee S, Seo MS, Park SB, Kurtz A, Kang SK, et al. (2010). Histone deacetylase controls adult stem cell aging by balancing the expression of polycomb genes and jumonji domain containing 3. Cell Mol Life Sci, 67:1165-1176.
Pan H, Guan D, Liu X, Li J, Wang L, Wu J, et al. (2016). SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res, 26:190-205.
Choi MR, In YH, Park J, Park T, Jung KH, Chai JC, et al. (2012). Genome-scale DNA methylation pattern profiling of human bone marrow mesenchymal stem cells in long-term culture. Exp Mol Med, 44:503-512.