An Unbiased Assessment of the Role of Imprinted Genes in an Intergenerational Model of Developmental Programming
Environmental factors during early life are critical for the later metabolic health of the individual and of future progeny. In our obesogenic environment, it is of great socioeconomic importance to investigate the mechanisms that contribute to the risk of metabolic ill health. Imprinted genes, a class of functionally mono-allelic genes critical for early growth and metabolic axis development, have been proposed to be uniquely susceptible to environmental change. Furthermore, it has also been suggested that perturbation of the epigenetic reprogramming of imprinting control regions (ICRs) may play a role in phenotypic heritability following early life insults. Alternatively, the presence of multiple layers of epigenetic regulation may in fact protect imprinted genes from such perturbation. Unbiased investigation of these alternative hypotheses requires assessment of imprinted gene expression in the context of the response of the whole transcriptome to environmental assault. We therefore analyse the role of imprinted genes in multiple tissues in two affected generations of an established murine model of the developmental origins of health and disease using microarrays and quantitative RT–PCR. We demonstrate that, despite the functional mono-allelicism of imprinted genes and their unique mechanisms of epigenetic dosage control, imprinted genes as a class are neither more susceptible nor protected from expression perturbation induced by maternal undernutrition in either the F1 or the F2 generation compared to other genes. Nor do we find any evidence that the epigenetic reprogramming of ICRs in the germline is susceptible to nutritional restriction. However, we propose that those imprinted genes that are affected may play important roles in the foetal response to undernutrition and potentially its long-term sequelae. We suggest that recently described instances of dosage regulation by relaxation of imprinting are rare and likely to be highly regulated.
Vyšlo v časopise:
An Unbiased Assessment of the Role of Imprinted Genes in an Intergenerational Model of Developmental Programming. PLoS Genet 8(4): e32767. doi:10.1371/journal.pgen.1002605
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002605
Souhrn
Environmental factors during early life are critical for the later metabolic health of the individual and of future progeny. In our obesogenic environment, it is of great socioeconomic importance to investigate the mechanisms that contribute to the risk of metabolic ill health. Imprinted genes, a class of functionally mono-allelic genes critical for early growth and metabolic axis development, have been proposed to be uniquely susceptible to environmental change. Furthermore, it has also been suggested that perturbation of the epigenetic reprogramming of imprinting control regions (ICRs) may play a role in phenotypic heritability following early life insults. Alternatively, the presence of multiple layers of epigenetic regulation may in fact protect imprinted genes from such perturbation. Unbiased investigation of these alternative hypotheses requires assessment of imprinted gene expression in the context of the response of the whole transcriptome to environmental assault. We therefore analyse the role of imprinted genes in multiple tissues in two affected generations of an established murine model of the developmental origins of health and disease using microarrays and quantitative RT–PCR. We demonstrate that, despite the functional mono-allelicism of imprinted genes and their unique mechanisms of epigenetic dosage control, imprinted genes as a class are neither more susceptible nor protected from expression perturbation induced by maternal undernutrition in either the F1 or the F2 generation compared to other genes. Nor do we find any evidence that the epigenetic reprogramming of ICRs in the germline is susceptible to nutritional restriction. However, we propose that those imprinted genes that are affected may play important roles in the foetal response to undernutrition and potentially its long-term sequelae. We suggest that recently described instances of dosage regulation by relaxation of imprinting are rare and likely to be highly regulated.
Zdroje
1. FowdenALForheadAJ 2004 Endocrine mechanisms of intrauterine programming. Reproduction 127 515 526
2. BirdA 2007 Perceptions of epigenetics. Nature 447 396 398
3. WeaverICCervoniNChampagneFAD'AlessioACSharmaS 2004 Epigenetic programming by maternal behavior. Nat Neurosci 7 847 854
4. ChampagneFAWeaverICDiorioJDymovSSzyfM 2006 Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology 147 2909 2915
5. ParkJHStoffersDANichollsRDSimmonsRA 2008 Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 118 2316 2324
6. RaychaudhuriNRaychaudhuriSThamotharanMDevaskarSU 2008 Histone code modifications repress glucose transporter 4 expression in the intrauterine growth-restricted offspring. J Biol Chem 283 13611 13626
7. MurgatroydCPatchevAVWuYMicaleVBockmuhlY 2009 Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 12 1559 1566
8. SandoviciISmithNHNitertMDAckers-JohnsonMUribe-LewisS 2011 Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci U S A
9. BarkerDJ 1998 In utero programming of chronic disease. Clin Sci (Lond) 95 115 128
10. KaatiGBygrenLOEdvinssonS 2002 Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Eur J Hum Genet 10 682 688
11. DrakeAJWalkerBR 2004 The intergenerational effects of fetal programming: non-genomic mechanisms for the inheritance of low birth weight and cardiovascular risk. J Endocrinol 180 1 16
12. ThamotharanMGargMOakSRogersLMPanG 2007 Transgenerational inheritance of the insulin-resistant phenotype in embryo-transferred intrauterine growth-restricted adult female rat offspring. Am J Physiol Endocrinol Metab 292 E1270 1279
13. PembreyMEBygrenLOKaatiGEdvinssonSNorthstoneK 2006 Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14 159 166
14. KaatiGBygrenLOPembreyMSjostromM 2007 Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet 15 784 790
15. Jimenez-ChillaronJCIsganaitisECharalambousMGestaSPentinat-PelegrinT 2009 Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes 58 460 468
16. NgSFLinRCLaybuttDRBarresROwensJA 2010 Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467 963 966
17. CaroneBRFauquierLHabibNSheaJMHartCE 2010 Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143 1084 1096
18. MorganHDSutherlandHGMartinDIWhitelawE 1999 Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23 314 318
19. RakyanVKChongSChampMECuthbertPCMorganHD 2003 Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci U S A 100 2538 2543
20. CropleyJESuterCMBeckmanKBMartinDI 2006 Germ-line epigenetic modification of the murine A vy allele by nutritional supplementation. Proc Natl Acad Sci U S A 103 17308 17312
21. JirtleRLSkinnerMK 2007 Environmental epigenomics and disease susceptibility. Nat Rev Genet 8 253 262
22. CharalambousMda RochaSTFerguson-SmithAC 2007 Genomic imprinting, growth control and the allocation of nutritional resources: consequences for postnatal life. Curr Opin Endocrinol Diabetes Obes 14 3 12
23. RadfordEJFerronSRFerguson-SmithAC 2011 Genomic imprinting as an adaptative model of developmental plasticity. FEBS Lett 585 2059 2066
24. Jimenez-ChillaronJCHernandez-ValenciaMReamerCFisherSJosziA 2005 Beta-cell secretory dysfunction in the pathogenesis of low birth weight-associated diabetes: a murine model. Diabetes 54 702 711
25. LuiJCFinkielstainGPBarnesKMBaronJ 2008 An imprinted gene network that controls mammalian somatic growth is down-regulated during postnatal growth deceleration in multiple organs. Am J Physiol Regul Integr Comp Physiol 295 R189 196
26. MoothaVKLindgrenCMErikssonKFSubramanianASihagS 2003 PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34 267 273
27. DennisGJrShermanBTHosackDAYangJGaoW 2003 DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4 P3
28. Huang daWShermanBTLempickiRA 2009 Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4 44 57
29. ZhangJUnderwoodLED'ErcoleAJ 2001 Hepatic mRNAs up-regulated by starvation: an expression profile determined by suppression subtractive hybridization. FASEB J 15 1261 1263
30. HigamiYBargerJLPageGPAllisonDBSmithSR 2006 Energy restriction lowers the expression of genes linked to inflammation, the cytoskeleton, the extracellular matrix, and angiogenesis in mouse adipose tissue. J Nutr 136 343 352
31. LiRYZhangQHLiuZQiaoJZhaoSX 2006 Effect of short-term and long-term fasting on transcriptional regulation of metabolic genes in rat tissues. Biochem Biophys Res Commun 344 562 570
32. SelmanCKerrisonNDCoorayAPiperMDLingardSJ 2006 Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice. Physiol Genomics 27 187 200
33. ArnaudPMonkDHitchinsMGordonEDeanW 2003 Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark. Hum Mol Genet 12 1005 1019
34. KwongWYWildAERobertsPWillisACFlemingTP 2000 Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development 127 4195 4202
35. MuellerBRBaleTL 2008 Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 28 9055 9065
36. LiLKeverneEBAparicioSAIshinoFBartonSC 1999 Regulation of maternal behavior and offspring growth by paternally expressed Peg3. Science 284 330 333
37. CurleyJPPinnockSBDicksonSLThresherRMiyoshiN 2005 Increased body fat in mice with a targeted mutation of the paternally expressed imprinted gene Peg3. FASEB J 19 1302 1304
38. CurleyJPBartonSSuraniAKeverneEB 2004 Coadaptation in mother and infant regulated by a paternally expressed imprinted gene. Proc Biol Sci 271 1303 1309
39. GlasgowERyuSLYamashitaMZhangBJMutsugaN 2005 APeg3, a novel paternally expressed gene 3 antisense RNA transcript specifically expressed in vasopressinergic magnocellular neurons in the rat supraoptic nucleus. Brain Res Mol Brain Res 137 143 151
40. Ferguson-SmithACPattiME 2011 You are what your dad ate. Cell Metab 13 115 117
41. SasakiHMatsuiY 2008 Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat Rev Genet 9 129 140
42. KonoTObataYYoshimzuTNakaharaTCarrollJ 1996 Epigenetic modifications during oocyte growth correlates with extended parthenogenetic development in the mouse. Nat Genet 13 91 94
43. ObataYKonoT 2002 Maternal primary imprinting is established at a specific time for each gene throughout oocyte growth. J Biol Chem 277 5285 5289
44. LuciferoDMannMRBartolomeiMSTraslerJM 2004 Gene-specific timing and epigenetic memory in oocyte imprinting. Hum Mol Genet 13 839 849
45. LiJYLees-MurdockDJXuGLWalshCP 2004 Timing of establishment of paternal methylation imprints in the mouse. Genomics 84 952 960
46. TomizawaSKobayashiHWatanabeTAndrewsSHataK 2011 Dynamic stage-specific changes in imprinted differentially methylated regions during early mammalian development and prevalence of non-CpG methylation in oocytes. Development 138 811 820
47. CoanPMAngioliniESandoviciIBurtonGJConstanciaM 2008 Adaptations in placental nutrient transfer capacity to meet fetal growth demands depend on placental size in mice. J Physiol 586 4567 4576
48. FerronSRCharalambousMRadfordEMcEwenKWildnerH 2011 Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature 475 381 385
49. BarlowDPStogerRHerrmannBGSaitoKSchweiferN 1991 The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature 349 84 87
50. LudwigTEggenschwilerJFisherPD'ErcoleAJDavenportML 1996 Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. Dev Biol 177 517 535
51. VarraultAGueydanCDelalbreABellmannAHoussamiS 2006 Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Dev Cell 11 711 722
52. SmithFMHoltLJGarfieldASCharalambousMKoumanovF 2007 Mice with a disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis, and insulin signaling during postnatal life. Mol Cell Biol 27 5871 5886
53. YuYYoonSOPoulogiannisGYangQMaXM 2011 Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332 1322 1326
54. HsuPPKangSARamesederJZhangYOttinaKA 2011 The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332 1317 1322
55. YoshimizuTMiroglioARipocheMAGaboryAVernucciM 2008 The H19 locus acts in vivo as a tumor suppressor. Proc Natl Acad Sci U S A 105 12417 12422
56. RelaixFWeiXJWuXSassoonDA 1998 Peg3/Pw1 is an imprinted gene involved in the TNF-NFkappaB signal transduction pathway. Nat Genet 18 287 291
57. YamaguchiATaniguchiMHoriOOgawaSTojoN 2002 Peg3/Pw1 is involved in p53-mediated cell death pathway in brain ischemia/hypoxia. J Biol Chem 277 623 629
58. JohnsonMDWuXAithmittiNMorrisonRS 2002 Peg3/Pw1 is a mediator between p53 and Bax in DNA damage-induced neuronal death. J Biol Chem 277 23000 23007
59. JiangXYuYYangHWAgarNYFradoL 2010 The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth. J Biol Chem 285 8472 8480
60. PinkstonJMGariganDHansenMKenyonC 2006 Mutations that increase the life span of C. elegans inhibit tumor growth. Science 313 971 975
61. VaziriHDessainSKNg EatonEImaiSIFryeRA 2001 hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107 149 159
62. ConstanciaMHembergerMHughesJDeanWFerguson-SmithA 2002 Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417 945 948
63. ConstanciaMAngioliniESandoviciISmithPSmithR 2005 Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems. Proc Natl Acad Sci U S A 102 19219 19224
64. CharalambousMCowleyMGeogheganFSmithFRadfordE 2010 Maternally-inherited Grb10 reduced placental size and efficiency. Dev Biol 337 1 8
65. EisenbergELevanonEY 2003 Human housekeeping genes are compact. Trends Genet 19 362 365
66. MoresiVGarcia-AlvarezGPristeraARizzutoEAlbertiniMC 2009 Modulation of caspase activity regulates skeletal muscle regeneration and function in response to vasopressin and tumor necrosis factor. PLoS ONE 4 e5570 doi:10.1371/journal.pone.0005570
67. RelaixFWengXMarazziGYangECopelandN 1996 Pw1, a novel zinc finger gene implicated in the myogenic and neuronal lineages. Dev Biol 177 383 396
68. TashJSBrachoGE 1998 Identification of phosphoproteins coupled to initiation of motility in live epididymal mouse sperm. Biochem Biophys Res Commun 251 557 563
69. WalshCPBestorTH 1999 Cytosine methylation and mammalian development. Genes Dev 13 26 34
70. TostJGutIG 2007 DNA methylation analysis by pyrosequencing. Nat Protoc 2 2265 2275
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 4
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- A Coordinated Interdependent Protein Circuitry Stabilizes the Kinetochore Ensemble to Protect CENP-A in the Human Pathogenic Yeast
- Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships
- Defective Membrane Remodeling in Neuromuscular Diseases: Insights from Animal Models
- Formation of Rigid, Non-Flight Forewings (Elytra) of a Beetle Requires Two Major Cuticular Proteins