Investigating the role of Sirtuins in cell reprogramming

  • Shin, Jaein (Laboratory of Stem Cells and Cell Reprogramming, Department of Biomedical Engineering (BKplus21 team), Dongguk University) ;
  • Kim, Junyeop (Laboratory of Stem Cells and Cell Reprogramming, Department of Biomedical Engineering (BKplus21 team), Dongguk University) ;
  • Park, Hanseul (Laboratory of Stem Cells and Cell Reprogramming, Department of Biomedical Engineering (BKplus21 team), Dongguk University) ;
  • Kim, Jongpil (Laboratory of Stem Cells and Cell Reprogramming, Department of Biomedical Engineering (BKplus21 team), Dongguk University)
  • Received : 2018.07.05
  • Published : 2018.10.31


Cell reprogramming has been considered a powerful technique in the regenerative medicine field. In addition to diverse its strengths, cell reprogramming technology also has several drawbacks generated during the process of reprogramming. Telomere shortening caused by the cell reprogramming process impedes the efficiency of cell reprogramming. Transcription factors used for reprogramming alter genomic contents and result in genetic mutations. Additionally, defective mitochondria functioning such as excessive mitochondrial fission leads to the limitation of pluripotency and ultimately reduces the efficiency of reprogramming. These problems including genomic instability and impaired mitochondrial dynamics should be resolved to apply cell reprograming in clinical research and to address efficiency and safety concerns. Sirtuin (NAD+-dependent histone deacetylase) has been known to control the chromatin state of the telomere and influence mitochondria function in cells. Recently, several studies reported that Sirtuins could control for genomic instability in cell reprogramming. Here, we review recent findings regarding the role of Sirtuins in cell reprogramming. And we propose that the manipulation of Sirtuins may improve defects that result from the steps of cell reprogramming.


Cell reprogramming;Genome stability;Induced pluripotent stem cells (iPSCs);Mytochondria dynamics;Sirtuins (Sirts)


Supported by : Ministry of Health & Welfare


  1. Morigi M, Perico L, Rota C et al (2015) Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury. J Clin Invest 125, 715-726
  2. Olichon A, Baricault L, Gas N et al (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278, 7743-7746
  3. Park SH, Ozden O, Jiang H et al (2011) Sirt3, mitochondrial ROS, ageing, and carcinogenesis. Int J Mol Sci 12, 6226-6239
  4. Ou X, Lee MR, Huang X, Messina-Graham S and Broxmeyer HE (2014) SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress. Stem Cells 32, 1183-1194
  5. Yoshii SR and Mizushima N (2015) Autophagy machinery in the context of mammalian mitophagy. Biochim Biophys Acta 1853, 2797-2801
  6. Eiyama A and Okamoto K (2015) PINK1/Parkin-mediated mitophagy in mammalian cells. Curr Opin Cell Biol 33, 95-101
  7. Koh H, Kim H, Kim MJ, Park J, Lee HJ and Chung J (2012) Silent information regulator 2 (Sir2) and Forkhead box O (FOXO) complement mitochondrial dysfunction and dopaminergic neuron loss in Drosophila PTEN-induced kinase 1 (PINK1) null mutant. J Biol Chem 287, 12750-12758
  8. Lim JH, Lee YM, Chun YS, Chen J, Kim JE and Park JW (2010) Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell 38, 864-878
  9. Qiu X, Brown K, Hirschey MD, Verdin E and Chen D (2010) Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 12, 662-667
  10. Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A and Gupta MP (2009) Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 119, 2758-2771
  11. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE and Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160, 189-200
  12. Chen H, Chomyn A and Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280, 26185-26192
  13. Christiansen EG (1949) Orientation of the mitochondria during mitosis. Nature 163, 361
  14. Cho DH, Nakamura T and Lipton SA (2010) Mitochondrial dynamics in cell death and neurodegeneration. Cell Mol Life Sci 67, 3435-3447
  15. Wilkerson DC and Sankar U (2011) Mitochondria: a sulfhydryl oxidase and fission GTPase connect mitochondrial dynamics with pluripotency in embryonic stem cells. Int J Biochem Cell Biol 43, 1252-1256
  16. Cipolat S, Martins de Brito O, Dal Zilio B and Scorrano L (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A 101, 15927-15932
  17. Son MJ, Kwon Y, Son MY et al (2015) Mitofusins deficiency elicits mitochondrial metabolic reprogramming to pluripotency. Cell Death Differ 22, 1957-1969
  18. Tanno M, Sakamoto J, Miura T, Shimamoto K and Horio Y (2007) Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J Biol Chem 282, 6823-6832
  19. Bell EL and Guarente L (2011) The SirT3 divining rod points to oxidative stress. Mol Cell 42, 561-568
  20. Giralt A, Hondares E, Villena JA et al (2011) Peroxisome proliferator-activated receptor-gamma coactivator-1alpha controls transcription of the Sirt3 gene, an essential component of the thermogenic brown adipocyte phenotype. J Biol Chem 286, 16958-16966
  21. Botta G, De Santis LP and Saladino R (2012) Current advances in the synthesis and antitumoral activity of SIRT1-2 inhibitors by modulation of p53 and pro-apoptotic proteins. Curr Med Chem 19, 5871-5884
  22. Villalba JM and Alcain FJ (2012) Sirtuin activators and inhibitors. Biofactors 38, 349-359
  23. Verdin E, Hirschey MD, Finley LW and Haigis MC (2010) Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci 35, 669-675
  24. Wang TT, Schoene NW, Kim EK and Kim YS (2013) Pleiotropic effects of the sirtuin inhibitor sirtinol involves concentration-dependent modulation of multiple nuclear receptor-mediated pathways in androgen-responsive prostate cancer cell LNCaP. Mol Carcinog 52, 676-685
  25. Peck B, Chen CY, Ho KK et al (2010) SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol Cancer Ther 9, 844-855
  26. Naia L and Rego AC (2015) Sirtuins: double players in Huntington's disease. Biochim Biophys Acta 1852, 2183-2194
  27. Chen J, Zhou Y, Mueller-Steiner S et al (2005) SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem 280, 40364-40374
  28. Risitano R, Curro M, Cirmi S et al (2014) Flavonoid fraction of Bergamot juice reduces LPS-induced inflammatory response through SIRT1-mediated NF-kappaB inhibition in THP-1 monocytes. PLoS One 9, e107431
  29. Polyakova O, Borman S, Grimley R, Vamathevan J, Hayes B and Solari R (2012) Identification of novel interacting partners of Sirtuin6. PLoS One 7, e51555
  30. Mopert K, Hajek P, Frank S, Chen C, Kaufmann J and Santel A (2009) Loss of Drp1 function alters OPA1 processing and changes mitochondrial membrane organization. Exp Cell Res 315, 2165-2180
  31. Chaudhary N and Pfluger PT (2009) Metabolic benefits from Sirt1 and Sirt1 activators. Curr Opin Clin Nutr Metab Care 12, 431-437
  32. Bruckbauer A, Zemel MB, Thorpe T et al (2012) Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice. Nutr Metab (Lond) 9, 77
  33. Chauhan D, Bandi M, Singh AV et al (2011) Preclinical evaluation of a novel SIRT1 modulator SRT1720 in multiple myeloma cells. Br J Haematol 155, 588-598
  34. Lahusen TJ and Deng CX (2015) SRT1720 induces lysosomal-dependent cell death of breast cancer cells. Mol Cancer Ther 14, 183-192
  35. Maya JD, Morello A, Repetto Y et al (2001) Trypanosoma cruzi: inhibition of parasite growth and respiration by oxazolo(thiazolo)pyridine derivatives and its relationship to redox potential and lipophilicity. Exp Parasitol 99, 1-6
  36. Vu CB, Bemis JE, Disch JS et al (2009) Discovery of imidazo[1,2-b]thiazole derivatives as novel SIRT1 activators. J Med Chem 52, 1275-1283
  37. Bonkowski MS and Sinclair DA (2016) Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol 17, 679-690
  38. Camins A, Sureda FX, Junyent F et al (2010) Sirtuin activators: designing molecules to extend life span. Biochim Biophys Acta 1799, 740-749
  39. Baur JA (2010) Biochemical effects of SIRT1 activators. Biochim Biophys Acta 1804, 1626-1634
  40. Gu XS, Wang ZB, Ye Z et al (2014) Resveratrol, an activator of SIRT1, upregulates AMPK and improves cardiac function in heart failure. Genet Mol Res 13, 323-335
  41. Vaziri H, Dessain SK, Ng Eaton E et al (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149-159
  42. Han MK, Song EK, Guo Y, Ou X, Mantel C and Broxmeyer HE (2008) SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular localization. Cell Stem Cell 2, 241-251
  43. Katada S, Imhof A and Sassone-Corsi P (2012) Connecting threads: epigenetics and metabolism. Cell 148, 24-28
  44. Ryall JG, Dell'Orso S, Derfoul A et al (2015) The NAD(+)-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells. Cell Stem Cell 16, 171-183
  45. Zwaans BM and Lombard DB (2014) Interplay between sirtuins, MYC and hypoxia-inducible factor in cancerassociated metabolic reprogramming. Dis Model Mech 7, 1023-1032
  46. Tennen RI, Bua DJ, Wright WE and Chua KF (2011) SIRT6 is required for maintenance of telomere position effect in human cells. Nat Commun 2, 433
  47. Kugel S and Mostoslavsky R (2014) Chromatin and beyond: the multitasking roles for SIRT6. Trends Biochem Sci 39, 72-81
  48. Michishita E, McCord RA, Boxer LD et al (2009) Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle 8, 2664-2666
  49. Toiber D, Erdel F, Bouazoune K et al (2013) SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol Cell 51, 454-468
  50. Galleano I, Schiedel M, Jung M, Madsen AS and Olsen CA (2016) A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay: Substrate Screening and Inhibitor Evaluation. J Med Chem 59, 1021-1031
  51. Lee S, Park JR, Seo MS et al (2009) Histone deacetylase inhibitors decrease proliferation potential and multilineage differentiation capability of human mesenchymal stem cells. Cell Prolif 42, 711-720
  52. Michishita E, McCord RA, Berber E et al (2008) SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492-496
  53. Chen T, Shen L, Yu J et al (2011) Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell 10, 908-911
  54. Huangfu D, Maehr R, Guo W et al (2008) Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 26, 795-797
  55. Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P and Reinberg D (2004) Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell 16, 93-105
  56. Zhang ZN, Chung SK, Xu Z and Xu Y (2014) Oct4 maintains the pluripotency of human embryonic stem cells by inactivating p53 through Sirt1-mediated deacetylation. Stem Cells 32, 157-165
  57. Etchegaray JP, Chavez L, Huang Y et al (2015) The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine. Nat Cell Biol 17, 545-557
  58. Peng CH, Cherng JY, Chiou GY et al (2011) Delivery of Oct4 and SirT1 with cationic polyurethanes-short branch PEI to aged retinal pigment epithelium. Biomaterials 32, 9077-9088
  59. Liu PY, Xu N, Malyukova A et al (2013) The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death Differ 20, 503-514
  60. Mao B, Zhao G, Lv X et al (2011) Sirt1 deacetylates c-Myc and promotes c-Myc/Max association. Int J Biochem Cell Biol 43, 1573-1581
  61. Prigione A, Fauler B, Lurz R, Lehrach H and Adjaye J (2010) The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. Stem Cells 28, 721-733
  62. Mandal S, Lindgren AG, Srivastava AS, Clark AT and Banerjee U (2011) Mitochondrial function controls proliferation and early differentiation potential of embryonic stem cells. Stem Cells 29, 486-495
  63. Sathananthan H, Pera M and Trounson A (2002) The fine structure of human embryonic stem cells. Reprod Biomed Online 4, 56-61
  64. Han H, Irimia M, Ross PJ et al (2013) MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature 498, 241-245
  65. Wang L, Ye X, Zhao Q et al (2014) Drp1 is dispensable for mitochondria biogenesis in induction to pluripotency but required for differentiation of embryonic stem cells. Stem Cells Dev 23, 2422-2434
  66. Otera H and Mihara K (2011) Molecular mechanisms and physiologic functions of mitochondrial dynamics. J Biochem 149, 241-251
  67. Ramanathan A and Schreiber SL (2009) Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci U S A 106, 22229-22232
  68. Wang S, Xia P, Ye B, Huang G, Liu J and Fan Z (2013) Transient activation of autophagy via Sox2-mediated suppression of mTOR is an important early step in reprogramming to pluripotency. Cell Stem Cell 13, 617-625
  69. Greer EL, Dowlatshahi D, Banko MR et al (2007) An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 17, 1646-1656
  70. Wang Z, Zang C, Rosenfeld JA et al (2008) Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet 40, 897-903
  71. Marion RM and Blasco MA (2010) Telomere rejuvenation during nuclear reprogramming. Curr Opin Genet Dev 20, 190-196
  72. Yehezkel S, Rebibo-Sabbah A, Segev Y et al (2011) Reprogramming of telomeric regions during the generation of human induced pluripotent stem cells and subsequent differentiation into fibroblast-like derivatives. Epigenetics 6, 63-75
  73. Pasi CE, Dereli-Oz A, Negrini S et al (2011) Genomic instability in induced stem cells. Cell Death Differ 18, 745-753
  74. Lopez-Contreras AJ, Gutierrez-Martinez P, Specks J, Rodrigo-Perez S and Fernandez-Capetillo O (2012) An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation. J Exp Med 209, 455-461
  75. Ruiz S, Lopez-Contreras AJ, Gabut M et al (2015) Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem cells. Nat Commun 6, 8036
  76. Mishra P and Chan DC (2014) Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol 15, 634-646
  77. Ji J, Sharma V, Qi S et al (2014) Antioxidant supplementation reduces genomic aberrations in human induced pluripotent stem cells. Stem Cell Reports 2, 44-51
  78. Facucho-Oliveira JM, Alderson J, Spikings EC, Egginton S and St John JC (2007) Mitochondrial DNA replication during differentiation of murine embryonic stem cells. J Cell Sci 120, 4025-4034
  79. Moussaieff A, Rouleau M, Kitsberg D et al (2015) Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab 21, 392-402
  80. Banito A, Rashid ST, Acosta JC et al (2009) Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev 23, 2134-2139
  81. Kimura H, Hayashi-Takanaka Y, Stasevich TJ and Sato Y (2015) Visualizing posttranslational and epigenetic modifications of endogenous proteins in vivo. Histochem Cell Biol 144, 101-109
  82. Xiao Y and Chen J (2013) Proteomics approaches in the identification of molecular signatures of mesenchymal stem cells. Adv Biochem Eng Biotechnol 129, 153-176
  83. Mu WL, Wang YJ, Xu P et al (2015) Sox2 Deacetylation by Sirt1 Is Involved in Mouse Somatic Reprogramming. Stem Cells 33, 2135-2147
  84. Mostoslavsky R, Chua KF, Lombard DB et al (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315-329
  85. Laurent LC, Ulitsky I, Slavin I et al (2011) Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8, 106-118
  86. Taapken SM, Nisler BS, Newton MA et al (2011) Karotypic abnormalities in human induced pluripotent stem cells and embryonic stem cells. Nat Biotechnol 29, 313-314
  87. Araten DJ, Golde DW, Zhang RH et al (2005) A quantitative measurement of the human somatic mutation rate. Cancer Res 65, 8111-8117
  88. Morin GB (1989) The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59, 521-529
  89. Vaziri H, Chapman KB, Guigova A et al (2010) Spontaneous reversal of the developmental aging of normal human cells following transcriptional reprogramming. Regen Med 5, 345-363
  90. Takahashi K and Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676
  91. Rando TA and Chang HY (2012) Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 148, 46-57
  92. Yu J, Vodyanik MA, Smuga-Otto K et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920
  93. Blasco MA, Serrano M and Fernandez-Capetillo O (2011) Genomic instability in iPS: time for a break. EMBO J 30, 991-993
  94. Suva ML, Riggi N and Bernstein BE (2013) Epigenetic reprogramming in cancer. Science 339, 1567-1570
  95. Ruiz S, Panopoulos AD, Herrerias A et al (2011) A high proliferation rate is required for cell reprogramming and maintenance of human embryonic stem cell identity. Curr Biol 21, 45-52
  96. Lopez-Otin C, Blasco MA, Partridge L, Serrano M and Kroemer G (2013) The hallmarks of aging. Cell 153, 1194-1217
  97. Marion RM, Strati K, Li H et al (2009) Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell 4, 141-154
  98. Weissbein U, Benvenisty N and Ben-David U (2014) Quality control: Genome maintenance in pluripotent stem cells. J Cell Biol 204, 153-163
  99. Folmes CD, Nelson TJ, Martinez-Fernandez A et al (2011) Somatic oxidative bioenergetics transitions into pluripotencydependent glycolysis to facilitate nuclear reprogramming. Cell Metab 14, 264-271