Asymmetric Strand Segregation: Epigenetic Costs of Genetic Fidelity?
Asymmetric strand segregation has been proposed as a mechanism to minimize effective mutation rates in epithelial tissues. Under asymmetric strand segregation, the double-stranded molecule that contains the oldest DNA strand is preferentially targeted to the somatic stem cell after each round of DNA replication. This oldest DNA strand is expected to have fewer errors than younger strands because some of the errors that arise on daughter strands during their synthesis fail to be repaired. Empirical findings suggest the possibility of asymmetric strand segregation in a subset of mammalian cell lineages, indicating that it may indeed function to increase genetic fidelity. However, the implications of asymmetric strand segregation for the fidelity of epigenetic information remain unexplored. Here, I explore the impact of strand-segregation dynamics on epigenetic fidelity using a mathematical-modelling approach that draws on the known molecular mechanisms of DNA methylation and existing rate estimates from empirical methylation data. I find that, for a wide range of starting methylation densities, asymmetric—but not symmetric—strand segregation leads to systematic increases in methylation levels if parent strands are subject to de novo methylation events. I found that epigenetic fidelity can be compromised when enhanced genetic fidelity is achieved through asymmetric strand segregation. Strand segregation dynamics could thus explain the increased DNA methylation densities that are observed in structured cellular populations during aging and in disease.
Vyšlo v časopise:
Asymmetric Strand Segregation: Epigenetic Costs of Genetic Fidelity?. PLoS Genet 5(6): e32767. doi:10.1371/journal.pgen.1000509
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1000509
Souhrn
Asymmetric strand segregation has been proposed as a mechanism to minimize effective mutation rates in epithelial tissues. Under asymmetric strand segregation, the double-stranded molecule that contains the oldest DNA strand is preferentially targeted to the somatic stem cell after each round of DNA replication. This oldest DNA strand is expected to have fewer errors than younger strands because some of the errors that arise on daughter strands during their synthesis fail to be repaired. Empirical findings suggest the possibility of asymmetric strand segregation in a subset of mammalian cell lineages, indicating that it may indeed function to increase genetic fidelity. However, the implications of asymmetric strand segregation for the fidelity of epigenetic information remain unexplored. Here, I explore the impact of strand-segregation dynamics on epigenetic fidelity using a mathematical-modelling approach that draws on the known molecular mechanisms of DNA methylation and existing rate estimates from empirical methylation data. I find that, for a wide range of starting methylation densities, asymmetric—but not symmetric—strand segregation leads to systematic increases in methylation levels if parent strands are subject to de novo methylation events. I found that epigenetic fidelity can be compromised when enhanced genetic fidelity is achieved through asymmetric strand segregation. Strand segregation dynamics could thus explain the increased DNA methylation densities that are observed in structured cellular populations during aging and in disease.
Zdroje
1. CairnsJ
1975 Mutation, selection and the natural history of cancer. Nature 255 197 200
2. LarkKG
ConsigliRA
MinochaHC
1966 Segregation of sister chromatids in mammalian cells. Science 154 1202 1205
3. KarpowiczP
MorsheadC
KamA
JervisE
RamunasJ
2005 Support for the immortal strand hypothesis: neural stem cells partition DNA asymmetrically in vitro. J Cell Biol 170 721 732
4. SmithGH
2005 Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development 132 681 687
5. ShininV
Gayraud-MorelB
GomesD
TajbakhshS
2006 Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nat Cell Biol 8 677 687
6. KielMJ
HeS
AshkenaziR
GentrySN
TetaM
2007 Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature 449 238 242
7. SotiropoulouP
CandiA
BlanpainC
2008 The majority of multipotent epidermal stem cells do not protect their genome by asymmetrical chromosome segregation. Stem Cells 26 2964 73
8. KlarAJ
1987 Differentiated parental DNA strands confer developmental asymmetry on daughter cells in fission yeast. Nature 326 466 470
9. KlarAJ
1994 A model for specification of the left-right axis in vertebrates. Trends Genet 10 392 396
10. KlarAJS
2004 A genetic mechanism implicates chromosome 11 in schizophrenia and bipolar diseases. Genetics 167 1833 1840
11. MerokJR
LansitaJA
TunsteadJR
SherleyJL
2002 Cosegregation of chromosomes containing immortal DNA strands in cells that cycle with asymmetric stem cell kinetics. Cancer Res 62 6791 6795
12. LiuSV
2005 Linking DNA aging with cell aging and combining genetics with epigenetics. Logical Biology 5 51 55
13. CairnsJ
2006 Cancer and the immortal strand hypothesis. Genetics 174 1069 1072
14. RandoTA
2007 The immortal strand hypothesis: segregation and reconstruction. Cell 129 1239 1243
15. LewDJ
BurkeDJ
DuttaA
2008 The immortal strand hypothesis: how could it work? Cell 133 21 23
16. LorinczMC
SchubelerD
HutchinsonSR
DickersonDR
GroudineM
2002 DNA methylation density inuences the stability of an epigenetic imprint and Dnmt3a/b-independent de novo methylation. Mol Cell Biol 22 7572 7580
17. LansdorpPM
2007 Immortal strands? Give me a break. Cell 129 1244 1247
18. KimJY
TavareS
ShibataD
2005 Counting human somatic cell replications: methylation mirrors endometrial stem cell divisions. Proc Natl Acad Sci U S A 102 17739 17744
19. KimJY
BeartRW
ShibataD
2005 Stability of colon stem cell methylation after neo-adjuvant therapy in a patient with attenuated familial adenomatous polyposis. BMC Gastroenterol 5 19
20. StögerR
KajimuraTM
BrownWT
LairdCD
1997 Epigenetic variation illustrated by DNA methylation patterns of the fragile-X gene FMR1. Hum Mol Genet 6 1791 1801
21. BjornssonHT
SigurdssonMI
FallinMD
IrizarryRA
AspelundT
2008 Intra-individual change over time in DNA methylation with familial clustering. JAMA 299 2877 2883
22. SandoviciI
NaumovaAK
LeppertM
LinaresY
SapienzaC
2004 A longitudinal study of X-inactivation ratio in human females. Hum Genet 115 387 392
23. SandoviciI
LeppertM
HawkPR
SuarezA
LinaresY
2003 Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions. Hum Mol Genet 12 1569 1578
24. WongDJ
FosterSA
GallowayDA
ReidBJ
1999 Progressive region-specific de novo methylation of the p16 CpG island in primary human mammary epithelial cell strains during escape from M(0) growth arrest. Mol Cell Biol 19 5642 5651
25. GradyWM
2005 Epigenetic events in the colorectum and in colon cancer. Biochem Soc Trans 33 684 688
26. SmithE
De YoungNJ
PaveySJ
HaywardNK
NancarrowDJ
2008 Similarity of aberrant DNA methylation in Barrett's esophagus and esophageal adenocarcinoma. Mol Cancer 7 75
27. LeonhardtH
PageAW
WeierHU
BestorTH
1992 A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71 865 873
28. OkanoM
BellDW
HaberDA
LiE
1999 DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99 247 257
29. YokochiT
RobertsonKD
2002 Preferential methylation of unmethylated DNA by mammalian de novo DNA methyltransferase Dnmt3a. J Biol Chem 277 11735 11745
30. HsiehCL
1999 In vivo activity of murine de novo methyltransferases, Dnmt3a and Dnmt3b. Mol Cell Biol 19 8211 8218
31. GenereuxDP
MinerBE
BergstromCT
LairdCD
2005 A population-epigenetic model to infer site-specific methylation rates from double-stranded DNA methylation patterns. Proc Natl Acad Sci U S A 102 5802 5807
32. RazinA
WebbC
SzyfM
YisraeliJ
RosenthalA
1984 Variations in DNA methylation during mouse cell differentiation in vivo and in vitro. Proc Natl Acad Sci U S A 81 2275 2279
33. AdamsRL
1971 Methylation of newly synthesized and older deoxyribonucleic acid. Biochem J 123 38P
34. SchneidermanMH
BillenD
1973 Methylation rapidly reannealing DNA during the cell cycle of Chinese hamster cells. Biochim Biophys Acta 308 352 360
35. BirdAP
1978 Use of restriction enzymes to study eukaryotic DNA methylation: II. the symmetry of methylated sites supports semi-conservative copying of the methylation pattern. J Mol Biol 118 49 60
36. KapplerJW
1970 The kinetics of DNA methylation in cultures of a mouse adrenal cell line. J Cell Physiol 75 21 31
37. OttoSP
WalbotV
1990 DNA methylation in eukaryotes: kinetics of demethylation and de novo methylation during the life cycle. Genetics 124 429 437
38. NicolasP
KimKM
ShibataD
TavareS
2007 The stem cell population of the human colon crypt: analysis via methylation patterns. PLoS Comput Biol 3 e28
39. PottenCS
1998 Stem cells in gastrointestinal epithelium: numbers, characteristics and death. Philos Trans R Soc Lond B Biol Sci 353 821 830
40. PfeiferGP
SteigerwaldSD
HansenRS
GartlerSM
RiggsAD
1990 Polymerase chain reactionaided genomic sequencing of an X chromosome-linked CpG island: methylation patterns suggest clonal inheritance, CpG site autonomy, and an explanation of activity state stability. Proc Natl Acad Sci U S A 87 8252 8256
41. LairdCD
PleasantND
ClarkAD
SneedenJL
HassanKMA
2004 Hairpin-bisulfite PCR: assessing epigenetic methylation patterns on complementary strands of individual DNA molecules. Proc Natl Acad Sci U S A 101 204 209
42. HermannA
GoyalR
JeltschA
2004 The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J Biol Chem 279 48350 48359
43. VilkaitisG
SuetakeI
KlimasauskasS
TajimaS
2005 Processive methylation of hemimethylated CpG sites by mouse Dnmt1 DNA methyltransferase. J Biol Chem 280 64 72
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2009 Číslo 6
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Cytoplasmic Streaming in : Disperse the Plug To Increase the Flow?
- Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations
- Is a Novel Locus for Waist Circumference: A Genome-Wide Association Study from the CHARGE Consortium
- Asymmetric Strand Segregation: Epigenetic Costs of Genetic Fidelity?