Top

Published in:

01-09-2014 | Original Article

Genome-wide analysis of DNA methylation in an APP/PS1 mouse model of Alzheimer’s disease

Authors: Lin Cong, Jianping Jia, Wei Qin, Yan Ren, Yongxin Sun

Published in: Acta Neurologica Belgica | Issue 3/2014

Abstract

To investigate aberrant genome-wide CpG methylation patterns in cortex brain tissue of APP/PS1 mice and as compared to controls, which allows for identification of novel disease-associated genes. This study investigates the genome-wide DNA methylation profiles of the cortex from APP/PS1 transgenic mice and control mice using the Roche NimbleGen chip platform. Functional analysis was then conducted by Ingenuity Pathways Analysis system. The methylated DNA fragments in the genome of each sample were enriched by MeDIP and the whole-genome interrogations were hybridized to the Roche NimbleGen Human DNA Methylation 3x720 K CpG Island Plus RefSeq Promoter Array that cover 15,980 CpG islands and 20,404 reference gene promoter regions of the entire human genome. Analysis reveals 2346 CpG sites representing 485 unique genes as potentially associated with AD disease status pending confirmation in additional study. At the same time, these hyper-methylated genes display familial aggregation. An impairment of the transforming growth factor-β1 (TGF-β1) signaling pathway has been demonstrated to be specific to the AD brain and, particularly, to the early phase of the disease, supporting a role for epigenetic change of TGF-β1 in AD pathology. In future research, we will focus on TGF-β1, as it appeared to be the most promising candidate for AD.

Lue LF, Brachova L, Civin WH, Rogers J (1996) Inflammation, a beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer’s disease neurodegeneration. J Neuropathol Exp Neurol 55:1083–1088PubMed

Mastroeni D, Mckee A, Grover A, Rogers J, Coleman PD (2009) Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease. PLoS One 4:e6617PubMedCrossRefPubMedCentral

Räihä I, Kaprio J, Koskenvuo M, Rajala T, Sourander L (1997) Alzheimer’s disease in twins. Biomed Pharmacother 51:101–104PubMedCrossRef

Bakulski KM, Dolinoy DC, Sartor MA, Paulson HL, Konen JR, Lieberman AP et al (2012) Genome-wide DNA methylation differences between late-onset Alzheimer’s disease and cognitively normal controls in human frontal cortex. J Alzheimer’s Dis 29:571–588

Felsenfeld G (2007) A brief history of epigenetics. In: Allis CD, Jenuwein T, Reinberg D (eds) Epigenetics. Cold Spring Harbor Laboratory Press, Maine, pp 15–22

Mastroeni D, Grover A, Elaine Delvaux E, Whiteside C, Coleman PD, Rogers J (2011) Epigenetic mechanisms in Alzheimer’s disease. Neurobiol Aging 32:1161–1180PubMedCrossRefPubMedCentral

Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D’Souza C, Fouse SD et al (2010) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466:253–257PubMedCrossRefPubMedCentral

Jin SG, Wu X, Li AX, Pfeifer GP (2011) Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res 39:5015–5024PubMedCrossRefPubMedCentral

Tohgi H, Utsugisawa K, Nagane Y, Yoshimura M, Genda Y, Ukitsu M (1999) Reduction with age in methylcytosine in the promoter region -224 approximately -101 of the amyloid precursor protein gene in autopsy human cortex. Brain Res Mol Brain Res 70:288–292PubMed

10.

Tohgi H, Utsugisawa K, Nagane Y, Yoshimura M, Ukitsu M, Genda Y (1999) The methylation status of cytosines in a tau gene promoter region alters with age to downregulate transcriptional activity in human cerebral cortex. Neurosci Lett 275:89–92PubMedCrossRef

11.

Barrachina M, Ferrer I (2009) DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain. J Neuropathol Exp Neurol 68:880–891PubMed

12.

Mill J (2011) Toward an integrated genetic and epigenetic approach to Alzheimer’s disease. Neurobiol Aging 32:1188–1191PubMedCrossRef

13.

Chouliaras L, Rutten BP, Kenis G, Peerbooms O, Visser PJ, Verhey F et al (2010) Epigenetic regulation in the pathophysiology of Alzheimer’s disease. Prog Neurobiol 90:498–510PubMedCrossRef

14.

Verret L, Jankowsky JL, Xu GM, Borchelt DR, Rampon C (2007) Alzheimer’s-type amyloidosis in transgenic mice impairs survival of newborn neurons derived from adult hippocampal neurogenesis. J Neurosci 27:6771–6780PubMedCrossRef

15.

Lalonde R, Kim HD, Fukuchi K (2004) Exploratory activity, anxiety, and motor coordination in bigenic APPswe t PS1/DeltaE9 mice. Neurosci Lett 369:156e61CrossRef

16.

Dewachter I, Reversé D, Caluwaerts N, Ris L, Kuipéri C, Van den Haute C et al (2002) Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci 22:3445e53

17.

Spuch C, Antequera D, Portero A, Orive G, Hernandez RM, Molina JA et al (2010) The effect of encapsulated VEGF-secreting cells on brain amyloid load and behavioral impairment in a mouse model of Alzheimer’s disease. Biomaterials 31:5608–5618PubMedCrossRef

18.

Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS et al (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol 9:R137PubMedCrossRefPubMedCentral

19.

Subramanian A, Tamayo P, Mootha VK et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545–15550PubMedCrossRefPubMedCentral

20.

Aguilera O, Fernandez AF, Munoz A, Fraga MF (2010) Epigenetics and environment: a complex relationship. J Appl Physiol 109:243–251PubMedCrossRef

21.

Dolinoy DC, Weidman JR, Jirtle RL (2007) Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol 23:297–307PubMedCrossRef

22.

Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8:253–262PubMedCrossRef

23.

Movassagh M, Choy MK, Goddard M, Bennett MR, Down TA, Foo RS (2010) Differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure. PLoS One 5:e8564PubMedCrossRefPubMedCentral

24.

Li M, Balch C, Montgomery JS, Jeong M, Chung JH, Yan P et al (2009) Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer. BMC Med Genomics 2:34PubMedCrossRefPubMedCentral

25.

Xin Yurong, Chanrion Benjamin, Liu Meng-Min (2010) Genome-wide divergence of DNA methylation marks in cerebral and cerebellar cortices. PLoS One 5(6):e11357PubMedCrossRefPubMedCentral

26.

Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, Lin C, Mucke L (1997) Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer’s disease. Nature 389(6651):603–606PubMedCrossRef

27.

Caraci F, Spampinato S, Sortino MA, Bosco P, Battaglia G, Bruno V, Drago F, Nicoletti F, Copani A (2012) Dysfunction of TGF-β1 signaling in Alzheimer’s disease: perspectives for neuroprotection. Cell Tissue Res 347(1):291–301PubMedCrossRef

28.

Ten Dijke P, Hill CS (2004) New insights into TGF-beta-Smad signalling. Trends Biochem Sci 29:265–273PubMedCrossRef

29.

Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-β regulation of immune responses. Annu Rev Immunol 24:99–146PubMedCrossRef

30.

Tesseur I, Zou K, Esposito L, Bard F, Berber E, Can JV et al (2006) Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer’s pathology. J Clin Invest 116:3060–3069PubMedCrossRefPubMedCentral

31.

Caraci F, Battaglia G, Bruno V, Bosco P, Carbonaro V, Giuffrida ML et al (2009) TGF-beta1 pathway as a new target for neuroprotection in Alzheimer’s disease. CNS Neurosci Ther 17:237–249PubMedCrossRef

32.

Wang H, Liu J, Zong Y, Xu Y, Zhu H, Deng W et al (2010) miR-106b aberrantly expressed in a double transgenic mouse model for Alzheimer’s disease targets TGF-β type II receptor. Brain Res 1357:166–174PubMed

33.

Lee HG, Ueda M, Zhu X, Perry G, Smith MA (2006) Ectopic expression of phospho-Smad2 in Alzheimer’s disease: uncoupling of the transforming growth factor-beta pathway? J Neurosci Res 84:1856–1861PubMedCrossRef

34.

35.

Ueberham U, Ueberham E, Gruschka H, Arendt T (2006) Altered subcellular location of phosphorylated Smads in Alzheimer’s disease. Eur J Neurosci 24:2327–2334PubMedCrossRef

36.

Chalmers KA, Love S (2007) Neurofibrillary tangles may interfere with Smad 2/3 signaling in neurons. J Neuropathol Exp Neurol 66:158–167PubMed

37.

Mocali A, Cedrola S, Della Malva N, Bontempelli M, Mitidieri VA, Bavazzano A et al (2004) Increased plasma levels of soluble CD40, together with the decrease of TGF beta 1, as possible differential markers of Alzheimer disease. Exp Gerontol 39:1555–1561PubMedCrossRef

38.

Juraskova B, Andrys C, Holmerova I, Solichova D, Hrnciarikova D, Vankova H et al (2010) Transforming growth factor beta and soluble endoglin in the healthy senior and in Alzheimer’s disease patients. J Nutr Health Aging 14:758–761PubMedCrossRef

39.

Luppi C, Fioravanti M, Bertolini B, Grugnetti A, Inguscio M, Guerriero F et al (2009) Growth factors decrease in subjects with mild to moderate Alzheimer’s disease (AD): potential correction with dehydroepiandrosteronesulphate (DHEAS). Arch Gerontol Geriatr 49:173–184PubMedCrossRef

40.

Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–322PubMedCrossRefPubMedCentral

41.

Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766PubMed

42.

Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3):383–421PubMedCrossRefPubMedCentral

Title: Genome-wide analysis of DNA methylation in an APP/PS1 mouse model of Alzheimer’s disease
Authors: Lin Cong
Jianping Jia
Wei Qin
Yan Ren
Yongxin Sun
Publication date: 01-09-2014
Publisher: Springer Milan
Published in: Acta Neurologica Belgica / Issue 3/2014
Print ISSN: 0300-9009
Electronic ISSN: 2240-2993
DOI: https://doi.org/10.1007/s13760-013-0267-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Genome-wide analysis of DNA methylation in an APP/PS1 mouse model of Alzheimer’s disease

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2014

Brainstem somatosensory and auditory evoked responses in central pontine myelinolysis

Postnatal interleukin-1β enhances adulthood seizure susceptibility and neuronal cell death after prolonged experimental febrile seizures in infantile rats

Safety and efficacy of natalizumab in Belgian multiple sclerosis patients: subgroup analysis of the natalizumab observational program

FLAIR fornix hyperintensity in VGKC-related autoimmune encephalitis

Suprasellar lymphoma masquerading as tuberculosis of the central nervous system

Isolated intramedullary cervical dermoid cyst