Biogerontology

, Volume 9, Issue 5, pp 325–334

Msh2 promoter region hypermethylation as a marker of aging-related deterioration in old retired female breeder mice

  • Juan C. Conde-Pérezprina
  • Armando Luna-López
  • Norma E. López-Diazguerrero
  • Pablo Damián-Matsumura
  • Alejandro Zentella
  • Mina Königsberg
Research Article

Abstract

Aging is a process where individuals decrease the performance of their physiological systems and cellular stress response, making them more susceptible to disease and death. The increase in DNA damage associated with age might be recognized as the accumulation of physiological and environmentally induced mutations accompanied with a decline in DNA repair. DNA mismatch repair (MMR) is the main postreplicative correction pathway, which is known to decrease with age. However, since infrequent occurrence of direct DNA damage contrasts with the extensive cell and tissue dysfunction seen in older individuals, the withdrawing of DNA-repairing systems might be also related to epigenetic changes, such as DNA methylation. It has been reported that the physiological stress related to breeding might accelerate the acquisition of aging-related markers; therefore, the aim of this work was to link age with epigenetic modifications in this animal population. Hence, the correlation of Msh2 gene silencing with the deterioration of breeding female mice associated to aging was determined. Combined bisulfite restriction analysis assay was used to compare methylation on DNA isolated from twelve-month-old retired breeders against nulliparous female mice aged-matched, and two-month-old young adults. Our experiments clearly reveal Msh2 promoter hypermethylation associated to the aging process. A higher degree methylation was additionally observed in breeding females DNA. Nevertheless, this additional methylation did not correlate with a further decrease Msh2 mRNA, suggesting that the increase in methylation in old retired breeder might account for further epigenetic changes that could additionally promote the aging process.

Keywords

Aging Breeding Epigenetics Methylation MSH2 Silencing 

Abbreviations

MMR

DNA mismatch repair

COBRA

Combined bisulfite restriction analysis assay

References

  1. Ahuja N, Issa JP (2000) Aging, methylation and cancer. Histol Histopathol 15:835–842PubMedGoogle Scholar
  2. Akintola AD, Crislip ZL, Catania JM, Zimmer WE, Burgahrdt RC, Parrish AR (2007) Promoter methylation is associated with the age-dependent loss of N-cadherin in the rat kidney. Am J Physiol Renal Physiol (in press)Google Scholar
  3. Altamirano A (1994) Manual de manejo de animales de laboratorio. Facultad de Estudios Superiores Veterinaria. Zaragoza UNAM, MéxicoGoogle Scholar
  4. Bennett-Baker PE, Wilkowski J, Burke DT (2003) Age-associated activation of epigenetically repressed genes in the mouse. Genetics 165:2055–2062PubMedGoogle Scholar
  5. Bernstein EE, Meissner A, Lander ES (2007) The mammalian epigenome. Cell 128:669–681PubMedCrossRefGoogle Scholar
  6. Bjornsson HT, Fallin MD, Feinberg AP (2004) An integrated epigenetic and genetic approach to common human disease. Trends Genet 20:350–358PubMedCrossRefGoogle Scholar
  7. Bohr VA (2002) Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells. Free Radic Biol Med 32:804–812PubMedCrossRefGoogle Scholar
  8. Campbell MR, Wang Y, Andrew SE, Liu Y (2006) MSH2 deficiency leads to chromosomal abnormalities, centrosome amplification, and telomere capping defect. Oncogene 25:2531–2536PubMedCrossRefGoogle Scholar
  9. Candore G, Balistreri CR, Listi F, Grimaldi MP, Vasto S, Colonna-Romano G, Franceschi C, Lio D, Caselli G, Caruso C (2006) Immunogenetics, gender, and longevity. Ann NY Acad Sci 1089:516–537PubMedCrossRefGoogle Scholar
  10. Chan PA, Duraisamy S, Miller PJ, Newell JA, McBride C, Bond JP, Raeveera T, Ollila S, Nyström M, Grimm AJ, Christodoulou J, Oetting WS, Greenbelatt MS (2007) Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR). Hum Mutat 28:683–693PubMedCrossRefGoogle Scholar
  11. Chomczynski P (1993) A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques 15:532–537PubMedGoogle Scholar
  12. Degtyareva NP, Greenwell P, Hofmann RE, Hengartner MO, Zhang L, Culotti JG, Petes TD (2002) Caenorhabditis elegans DNA mismatch repair gene msh-2 is required for microsatellite stability and maintenance of genome integrity. Proc Natl Acad Sci USA 99:2158–2163PubMedCrossRefGoogle Scholar
  13. Estes S, Phillips PC, Denver DR, Thomas WK, Lynch M (2004) Mutation accumulation in populations of varying size: the distribution of mutational effects for fitness correlates in Caenorhabditis elegans. Genetics 166:1269–1279PubMedCrossRefGoogle Scholar
  14. Feinberg AP, Oshimura M, Barrett JC (2002) Epigenetic mechanisms in human disease. Cancer Res 62:6784–6787PubMedGoogle Scholar
  15. Finch CE, Pike MC, Witten M (1990) Slow mortality rate accelerations during aging in some animals approximate that of humans. Science 249:902–905PubMedCrossRefGoogle Scholar
  16. Fraga MF, Agrelo R, Esteller M (2007) Cross-talk between aging and cancer: the epigenetic language. Ann NY Acad Sci 1100:60–74PubMedCrossRefGoogle Scholar
  17. Garcia-Manero G, Daniel J, Smith TL, Kornblau SM, Lee MS, Kantarjian HM, Issa JP (2002) DNA methylation of multiple promoter-associated CpG islands in adult acute lymphocytic leukemia. Clin Can Res 8:2217–2224Google Scholar
  18. Goldberg M, Rummelt C, Laerm A, Helmbold P, Holbach LM, Ballhausen WG (2006) Epigenetic silencing contributes to frequent loss of the fragile histidine triad tumour suppressor in basal cell carcinomas. Br J Dermatol 155:1154–1158PubMedCrossRefGoogle Scholar
  19. Grunau C, Sanchez C, Ehrlich M, Van der Bruggen P, Hindermann W, Rodriguez C, Krieger S, Dubeau L, Fiala E, De Sario A (2005) Frequent DNA hypomethylation of human juxtacentromeric BAGE loci in cancer. Genes Chrom Cancer 43:11–24PubMedCrossRefGoogle Scholar
  20. Harfe BD, Jinks-Robertson S (2000) Sequence composition and context effects on the generation and repair of frameshift intermediates in mononucleotide runs in Saccharomyces cerevisiae. Genetics 156:571–578PubMedGoogle Scholar
  21. Hasty P, Vijg J (2002) Aging. Genomic priorities in aging. Science 296:1250–1251PubMedCrossRefGoogle Scholar
  22. Hughes S, Jones LJ (2007) The use of whole genome amplified DNA as a control for methylation specific PCR, pyrosequencing, bisulfite sequencing and methylation-sensitive restriction enzyme PCR. BMC Mol Biol 8(1):91PubMedCrossRefGoogle Scholar
  23. Imam SZ, Karahalil B, Hogue BA, Souza-Pinto NC, Bohr VA (2006) Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse is altered in an age-dependent manner. Neurobiol Aging 27:1129–1136PubMedCrossRefGoogle Scholar
  24. Issa JP (2002) Epigenetic variation and human disease. J Nutr 132:2388S–2392SPubMedGoogle Scholar
  25. Issa JP (2003) Age-related epigenetic changes and the immune system. Clin Immunol 109:103–108PubMedCrossRefGoogle Scholar
  26. Issa JP (2007) DNA Methylation in cancer protocols. Bisulfite-PCR for Restriction Analysis and/or Sequencing. http://www.mdanderson.org/departments/methylation/display. Cited 11 Dic 2007. The University of Texas MD Anderson Cancer Center.
  27. Jiricny J (2006) The multifaceted mismatch-repair system. Nature Rev 7:335–346CrossRefGoogle Scholar
  28. Jun S, Kim TG, Ban C (2006) DNA mismatch repair system classical and fresh roles. FEBS J 273:1609–1619PubMedCrossRefGoogle Scholar
  29. Kim JY, Siegmund KD, Tavaté S, Shibata D (2005) Age-related human small intestine methylation: evidence for stem cell niches. BMC Med 3:10PubMedCrossRefGoogle Scholar
  30. Königsberg M, López-Diazguerrero NE, Rivera-Martinez LP, González-Puertos VY, González-Vieira R, Gutiérrez-Ruiz MC, Zentella A (2007) The physiological deterioration associated to breeding in female mice: a model for the study of senescence and aging. Comp Biochem Physiol A 146:695–701CrossRefGoogle Scholar
  31. López-Araiza H, Ventura JL, López-Diazguerrero NE, González-Marquez H, Gutiérrez-Ruíz MC, Zentella DA, Königsberg FM (2006) Organ- and Tissue-specific Alterations in the Anti-apoptotic Protein Bcl-2 in CD1 Female Mice of Different Ages. Biogerontology 7:63–67PubMedCrossRefGoogle Scholar
  32. López-Diazguerrero NE, Luna-López A, Gutiérrez-Ruiz MC, Zentella A, Konigsberg M (2005) Susceptibility of DNA to oxidative stressors in young and aging mice. Life Sci 77:2840–2854PubMedCrossRefGoogle Scholar
  33. Madia F, Gattazzo C, Fabrizio P, Longo VD (2007) A simple model system for age-dependent DNA damage and cancer. Mech Ageing Dev 128:45–49PubMedCrossRefGoogle Scholar
  34. Matos HR, Capelozzi VL, Gomes OF, Di Mascio P, Medeiros MH (2001) Lycopene inhibits DNA damage and liver necrosis in rats treated with ferric nitiolacetate. Arch Biochem Biophys 396:171–177PubMedCrossRefGoogle Scholar
  35. Matsuo K, Silke J, Gramatikoff K, Schaffner W (1994) The CpG-specific methylase SssI has topoisomerase activity in the presence of Mg2+. Nucleic Acids Res 22:5354–4359PubMedCrossRefGoogle Scholar
  36. Neri S, Pawelec G, Facchini A, Mariani E (2007) Microsatellite instability and compromised mismatch repair gene expression during in vitro passaging of monoclonal human T lymphocytes. Rejuvenation Res 10:145–156PubMedCrossRefGoogle Scholar
  37. Ottaviano Y, Issa JP, Parl FF, Smith HS, Baylin SB, Davidson NE (1994) Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res 54:2552–2555PubMedGoogle Scholar
  38. Park Y, Gerson SL (2005) DNA repair defects in stem cell function and aging. Ann Rev Med 56:495–508PubMedCrossRefGoogle Scholar
  39. Phelan JP, Rose MR (2005) Why dietary restriction substantially increases longevity in animal models but won’t in humans. Age Res Rev 4:339–350CrossRefGoogle Scholar
  40. Ravindran CR, Ticku MK (2005) Methylation of NMDA receptor NR2B gene as a function of age in the mouse brain. Neurosci Lett 380:223–228PubMedCrossRefGoogle Scholar
  41. Richardson B (2003) Impact of aging on DNA methylation. Age Res Rev 2:245–261CrossRefGoogle Scholar
  42. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmarkers J, Wisseman IL (2007) Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447:725–729PubMedCrossRefGoogle Scholar
  43. Russel ES (1964) Lifespan and aging patterns. In: Green EL (ed) Biology of the Laboratory Mouse. Dover Publications. Inc., New York, pp 685–692Google Scholar
  44. Schmitt E, Paquet C, Beauchemin M, Bertrand R (2007) DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis. J Zhejiang Univ Sci B 8:377–397PubMedCrossRefGoogle Scholar
  45. Siegmund KD, Connor CM, Campan M, Long TI, Weisenberg DJ, Biiniskiewicz D, Jeanish R, Laird PW, Akbarian S (2007) DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS ONE 2(9):e895PubMedCrossRefGoogle Scholar
  46. So K, Tamura G, Honda T, Homma N, Waki T, Togawa N, Nishizuka S, Motoyama T (2006) Multiple tumor suppressor genes are increasingly methylated with age in non-neoplastic gastric epithelia. Cancer Sci 97:1155–1158PubMedCrossRefGoogle Scholar
  47. Takahashi Y, Moriwaki S, Sugiyama Y, Endo Y, Yamazaki K, Mori T, Takigawa M, Inoue S (2005) Decreased gene expression responsible for post-ultraviolet DNA repair synthesis in aging: a possible mechanism of age-related reduction in DNA repair capacity. J Inv Dermatol 124:435–442CrossRefGoogle Scholar
  48. Tuirán R, Partida V, Mojarro O, Zúñiga E (2002) Tendencias y perspectivas de la fecundidad. La Situación Demográfica de México. Consejo Nacional de Población (CONAPO). México City, pp 29–48Google Scholar
  49. Villarreal-Molina MT, Aguilar-Salinas CA, Rodrıguez-Cruz M, Riano D, Villalobos-Comparan M, Coral-Vazquez R, Menjivar M, Yescas-Gomez P, Konigsoerg-Fainstein M, Romero-Hidalgo S, Tusie-Luna MT, Canizales-Quinteros S (2007) The ATP-binding cassette transporter A1 R230C variant affects HDL cholesterol levels and BMI in the Mexican population. Diabetes 56:1881–1887PubMedCrossRefGoogle Scholar
  50. Wang L, Hirayasu K, Ishisawa M, Kobayash Y (1994) Purification of genomic DNA from human whole blood by isopropanol-fractionation with concentrated Nal and SDS. Nucl Acids Res 22:1774–1775PubMedCrossRefGoogle Scholar
  51. Xiong Z, Laird PW (1997) COBRA: a sensitive and quantitative DNA methylation assay. Nucleic Acids Res 25:2532–2534PubMedCrossRefGoogle Scholar
  52. Xu XL, Yu J, Zhang HY, Sun MH, Gu J, Du X, Shi DR, Wang P, Yang ZH, Zhu JD (2004) Methylation profile of the promoter CpG islands of 31 genes that may contribute to colorectal carcinogenesis. World J Gastroenterol 10:3441–3454PubMedGoogle Scholar
  53. Yang AS, Estécio MRH, Doshi K, Kondo Y, Tajara EH, Issa JP (2004) A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucl Acids Res 32:1–6CrossRefGoogle Scholar
  54. Yuasa Y (2002) DNA methylation in cancer and ageing. Mech Ageing Dev 123:1649–1654PubMedCrossRefGoogle Scholar
  55. Zeng X, Kinsella TJ (2007) A novel role for DNA mismatch repair and the autophagic processing of chemotherapy drugs in human tumor cells. Autophagy 3:368–370PubMedGoogle Scholar
  56. Zúñiga E, Durán D, Logia S (2002) La salud reproductiva en las entidades federativas: una mirada a través de los índices de rezago. La Situación Demográfica de México. Consejo Nacional de Población (CONAPO). Mexico City, pp 49–66.Google Scholar
  57. Zurcher C, Van Zwieten MJ, Solleveld HA, Hollander CF (1982) The mouse in biomedical research. In: Foster HL, Small JD, Fox JG (eds) Experimental biology and oncology, Inc. New York, Academic Press, pp 325–345Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Juan C. Conde-Pérezprina
    • 1
    • 2
  • Armando Luna-López
    • 1
    • 2
  • Norma E. López-Diazguerrero
    • 1
  • Pablo Damián-Matsumura
    • 3
  • Alejandro Zentella
    • 4
  • Mina Königsberg
    • 1
  1. 1.Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la SaludUniversidad Autónoma Metropolitana-IztapalapaMexicoMexico
  2. 2.Programa de Posgrado en Biología ExperimentalUniversidad Autónoma Metropolitana-IztapalapaMexicoMexico
  3. 3.Depto. Biología de la Reproducción, DCBSUniversidad Autónoma Metropolitana-IztapalapaMexicoMexico
  4. 4.Depto. Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán” & Depto. Medicina Genómica y Toxicología AmbientalIIB-UNAMMexicoMexico

Personalised recommendations