SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer

Abstract

SIRT7, a sirtuin family member implicated in aging and disease, is a regulator of metabolism and stress responses. It remains elusive how human somatic stem cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during human mesenchymal stem cell (hMSC) aging and that SIRT7 deficiency accelerates senescence. Mechanistically, SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins, thus maintaining the repressive state of heterochromatin at nuclear periphery. Accordingly, deficiency of SIRT7 results in loss of heterochromatin, de-repression of the LINE1 retrotransposon (LINE1), and activation of innate immune signaling via the cGAS-STING pathway. These agingassociated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor. Together, these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.

Key words： SIRT7; stem cell; aging; LINE1; cGAS; STING

References

1 Anders S, Pyl PT, Huber W (2015) HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics (Oxford, England) 31:166–169

2 Araki S, Izumiya Y, Rokutanda T, Ianni A, Hanatani S, Kimura Y, Onoue Y, Senokuchi T, Yoshizawa T, Yasuda O (2015) Sirt7 contributes to myocardial tissue repair by maintaining transforming growth factor-beta signaling pathway. Circulation 132:1081–1093

3 Bao X, Liu Z, Zhang W, Gladysz K, Fung YME, Tian G, Xiong Y, Wong JWH, Yuen KWY, Li XD (2019) Glutarylation of Histone H4 Lysine 91 regulates chromatin dynamics. Mol Cell 76(660–675):e669

4 Barber MF, Michishita-Kioi E, Xi Y, Tasselli L, Kioi M, Moqtaderi Z, Tennen RI, Paredes S, Young NL, Chen K (2012) SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 487:114–118

5 Bickmore WA, van Steensel B (2013) Genome architecture: domain organization of interphase chromosomes. Cell 152:1270–1284

6 Bishop NA, Guarente L (2007) Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat Rev Genet 8:835–844

7 Bourque G, Burns KH, Gehring M, Gorbunova V, Seluanov A, Hammell M, Imbeault M, Izsvak Z, Levin HL, Macfarlan TS (2018) Ten things you should know about transposable elements. Genome Biol 19:199

8 Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ (2013) Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods 10:1213–1218

9 Castro-Diaz N, Ecco G, Coluccio A, Kapopoulou A, Yazdanpanah B, Friedli M, Duc J, Jang SM, Turelli P, Trono D (2014) Evolutionally dynamic L1 regulation in embryonic stem cells. Genes Dev 28:1397–1409

10 Chen J, Bardes EE, Aronow BJ, Jegga AG (2009) ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucl Acids Res 37:W305–311

11 Chen S, Blank MF, Iyer A, Huang B, Wang L, Grummt I, Voit R (2016) SIRT7-dependent deacetylation of the U3-55k protein controls pre-rRNA processing. Nat Commun 7:10734

12 Cheng F, Wang S, Song M, Liu Z, Liu P, Wang L, Wang Y, Zhao Q, Yan K, Chan P(2019) DJ-1 is dispensable for human stem cell homeostasis. Protein Cell 10:846–853

13 Cioffi M, Vallespinos-Serrano M, Trabulo SM, Fernandez-Marcos PJ, Firment AN, Vazquez BN, Vieira CR, Mulero F, Camara JA, Cronin UP (2015) MiR-93 controls adiposity via inhibition of Sirt7 and Tbx3. Cell Rep 12:1594–1605

14 Dai L, Huang Q, Boeke JD (2011) Effect of reverse transcriptase inhibitors on LINE-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition. BMC Biochem 12:18

15 De Cecco M, Criscione SW, Peckham EJ, Hillenmeyer S, Hamm EA, Manivannan J,Peterson AL, Kreiling JA, Neretti N, Sedivy JM (2013) Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12:247–256

16 De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, Caligiana A, Brocculi G, Adney EM, Boeke JD (2019) L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566:73–78

17 Deng L, Ren R, Liu Z, Song M, Li J, Wu Z, Ren X, Fu L, Li W, Zhang W (2019) Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis. Nat Commun 10:3329

18 Dimarino AM, Caplan AI, Bonfield TL (2013) Mesenchymal stem cells in tissue repair. Front Immunol 4:201

19 Finkel T, Deng CX, Mostoslavsky R (2009) Recent progress in the biology and physiology of sirtuins. Nature 460:587–591

20 Fu L, Hu Y, Song M, Liu Z, Zhang W, Yu FX, Wu J, Wang S, Izpisua Belmonte JC, Chan P(2019) Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis. PLoS Biol 17:e3000201

21 Garcia-Perez JL, Morell M, Scheys JO, Kulpa DA, Morell S, Carter CC, Hammer GD, Collins KL, O’Shea KS, Menendez P (2010) Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells. Nature 466:769–773

22 Geng L, Liu Z, Wang S, Sun S, Ma S, Liu X, Chan P, Sun L, Song M, Zhang W (2019) Low-dose quercetin positively regulates mouse healthspan. Protein Cell 10:770–775

23 Gorbunova V, Boeke JD, Helfand SL, Sedivy JM (2014) Human genomics. Sleeping dogs of the genome. Science 346:1187–1188

24 Grewal SI, Jia S(2007) Heterochromatin revisited. Nature reviews. Genetics 8:35–46

25 Guelen L, Pagie L, Brasset E, Meuleman W, Faza MB, Talhout W, Eussen BH, de Klein A, Wessels L, de Laat W (2008) Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453:948–951

26 Ha G, Roth A, Lai D, Bashashati A, Ding J, Goya R, Giuliany R, Rosner J, Oloumi A, Shumansky K (2012) Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triplenegative breast cancer. Genome Res 22:1995–2007

27 He X, Memczak S, Qu J, Belmonte JCI, Liu G-H (2020) Single-cell omics in ageing: a young and growing field. Nat Metab 2:293–302

28 Herskovits AZ, Guarente L (2013) Sirtuin deacetylases in neurodegenerative diseases of aging. Cell Res 23:746–758

29 Iyer-Bierhoff A, Krogh N, Tessarz P, Ruppert T, Nielsen H, Grummt I (2018) SIRT7-dependent deacetylation of fibrillarin controls histone H2A methylation and rRNA synthesis during the cell cycle. Cell Rep 25(2946–2954):e2945

30 Jones RB, Garrison KE, Wong JC, Duan EH, Nixon DF, Ostrowski MA (2008) Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition. PLoS ONE 3:e1547

31 Kim D, Langmead B, Salzberg SL (2015) HISAT: a fast spliced aligner with low memory requirements. Nat Methods 12:357–360

32 Kiran S, Oddi V, Ramakrishna G (2015) Sirtuin 7 promotes cellular survival following genomic stress by attenuation of DNA damage, SAPK activation and p53 response. Exp Cell Res 331:123–141

33 Kubben N, Misteli T (2017) Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases. Nat Rev Mol Cell Biol 18:595–609

34 Kubben N, Zhang W, Wang L, Voss TC, Yang J, Qu J, Liu GH, Misteli T (2016) Repression of the antioxidant NRF2 pathway in premature aging. Cell 165:1361–1374

35 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

36 Langmead B, Salzberg SL (2012) Fast gapped-read alignment with Bowtie 2. Nat Methods 9:357–359

37 Li L, Shi L, Yang S, Yan R, Zhang D, Yang J, He L, Li W, Yi X, Sun L (2016) SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. Nat Commun 7:12235

38 Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C (2011) Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472:221–225

39 Liu GH, Qu J, Suzuki K, Nivet E, Li M, Montserrat N, Yi F, Xu X, Ruiz S, Zhang W (2012) Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 491:603–607

40 Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217

41 Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell 16:4623–4635

42 Miura Y (2016) Human bone marrow mesenchymal stromal/stem cells: current clinical applications and potential for hematology. Int J Hematol 103:122–128

43 Mohrin M, Shin J, Liu Y, Brown K, Luo H, Xi Y, Haynes CM, Chen D (2015) Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347:1374–1377

44 Obeid M, Saber Sel D, Ismael Ael D, Hassanien E (2013) Mesenchymal stem cells promote hard-tissue repair after direct pulp capping. J Endod 39:626–631

45 Olive PL, Banath JP (2006) The comet assay: a method to measure DNA damage in individual cells. Nat Protoc 1:23–29

46 Pan H, Guan D, Liu X, Li J, Wang L, Wu J, Zhou J, Zhang W, Ren R, Zhang W (2016) SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res 26:190–205

47 Paredes S, Angulo-Ibanez M, Tasselli L, Carlson SM, Zheng W, Li TM, Chua KF (2018) The epigenetic regulator SIRT7 guards against mammalian cellular senescence induced by ribosomal DNA instability. The Journal of biological chemistry 293:11242–11250

48 Percharde M, Lin CJ, Yin Y, Guan J, Peixoto GA, Bulut-Karslioglu A, Biechele S, Huang B, Shen X, Ramalho-Santos M (2018) A LINE1-nucleolin partnership regulates early development and ESC identity. Cell 174(391–405):e319

49 Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT, Salzberg SL (2015) StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol 33:290–295

50 Ren R, Ocampo A, Liu GH, Izpisua Belmonte JC (2017) Regulation of stem cell aging by metabolism and epigenetics. Cell Metab 26:460–474

51 Ren X, Hu B, Song M, Ding Z, Dang Y, Liu Z, Zhang W, Ji Q, Ren R, Ding J (2019) Maintenance of nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis. Cell Rep 26 (3643–3656):e3647

52 Sanjana NE, Shalem O, Zhang F (2014) Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods 11:783–784

53 Secunda R, Vennila R, Mohanashankar AM, Rajasundari M, Jeswanth S, Surendran R (2015) Isolation, expansion and characterisation of mesenchymal stem cells from human bone marrow, adipose tissue, umbilical cord blood and matrix: a comparative study. Cytotechnology 67:793–807

54 Shin J, He M, Liu Y, Paredes S, Villanova L, Brown K, Qiu X, Nabavi N, Mohrin M, Wojnoonski K (2013) SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease. Cell Rep 5:654–665

55 Simon M, Van Meter M, Ablaeva J, Ke Z, Gonzalez RS, Taguchi T, De Cecco M, Leonova KI, Kogan V, Helfand SL (2019) LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab 29(871–885):e875

56 Singh PP, Demmitt BA, Nath RD, Brunet A (2019) The genetics of aging: a vertebrate perspective. Cell 177:200–220

57 Sridharan R, Gonzales-Cope M, Chronis C, Bonora G, McKee R, Huang C, Patel S, Lopez D, Mishra N, Pellegrini M (2013) Proteomic and genomic approaches reveal critical functions of developmental retardation in cynomolgus monkeys. Nature 560:661–665

58 Zhang, W., Qu, J., Liu, G.H., and Belmonte, J.C.I. (2020). The ageing epigenome and its rejuvenation. Nature reviews Molecular cell biology.

59 Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, Leboff MS, Glowacki J (2008) Age-related intrinsic changes in human bonemarrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell 7:335–343