Genome‑wide DNA methylation profiling in a rat model with vascular dementia

Park,Jong‑Min; Kim,Yoon  Ju; Song,Min  Kyung; Lee,Jae‑Min; Kim,Youn‑Jung

doi:10.3892/mmr.2018.8990

Genome‑wide DNA methylation profiling in a rat model with vascular dementia

Authors:
- Jong‑Min Park
- Yoon Ju Kim
- Min Kyung Song
- Jae‑Min Lee
- Youn‑Jung Kim
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Affiliations: Department of Nursing, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea, Department of Physiology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea, College of Nursing Science, Kyung Hee University, Seoul 02447, Republic of Korea
Published online on: May 8, 2018 https://doi.org/10.3892/mmr.2018.8990
Pages: 123-130
Copyright: © Park et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Vascular dementia (VaD), the second most prevalent type of dementia, is caused by reduced blood supply to the brain that results in cognitive impairment. Despite the efforts of numerous studies, the pathological mechanisms behind VaD remain unclear. The aim of the present study was to identify candidate genes that undergo changes in hippocampal DNA methylation owing to VaD. A genome‑wide DNA methylation analysis was performed, using methylated DNA‑binding domain sequencing. VaD model rats with cognitive impairment induced by bilateral common carotid artery occlusion were confirmed using the radial arm maze test. A total of 1,180 differentially methylated genes (DMGs) were identified, and functional annotation analysis revealed the DMGs to be enriched in 10 Gene Ontology biological processes. Network analysis using the STRING database indicated that seven genes were closely connected. Rats in the VaD model group demonstrated relative hypomethylation in the promoter region and increased mRNA expression of the hippocampal genes vascular endothelial growth factor (VEGFA) and kinase insert domain receptor, but only differences in VEGFA mRNA expression levels were determined to be statistically significant. In conclusion, these preliminary data from the functional annotation of hippocampal DMGs in the promoter region highlighted candidate genes for VaD that may contribute to the elucidation of its pathophysiology.

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1	Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, Luchsinger JA, Ogunniyi A, Perry EK, Potocnik F, et al: Alzheimer's disease and vascular dementia in developing countries: Prevalence, management, and risk factors. Lancet Neurol. 7:812–826. 2008. View Article : Google Scholar : PubMed/NCBI
2	Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W and Ferri CP: The global prevalence of dementia: A systematic review and metaanalysis. Alzheimers Dement. 9(63): 75. e22013.
3	Iadecola C: The pathobiology of vascular dementia. Neuron. 80:844–866. 2013. View Article : Google Scholar : PubMed/NCBI
4	Gill R, Tsung A and Billiar T: Linking oxidative stress to inflammation: Toll-like receptors. Free Radic Biol Med. 48:1121–1132. 2010. View Article : Google Scholar : PubMed/NCBI
5	Liu H and Zhang J: Cerebral hypoperfusion and cognitive impairment: The pathogenic role of vascular oxidative stress. Int J Neurosci. 122:494–499. 2012. View Article : Google Scholar : PubMed/NCBI
6	Park HR, Park M, Choi J, Park K, Chung HY and Lee J: A high-fat diet impairs neurogenesis: Involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett. 482:235–239. 2010. View Article : Google Scholar : PubMed/NCBI
7	Chen J, Cui X, Zacharek A, Cui Y, Roberts C and Chopp M: White matter damage and the effect of matrix metalloproteinases in type 2 diabetic mice after stroke. Stroke. 42:445–452. 2011. View Article : Google Scholar : PubMed/NCBI
8	Venkat P, Chopp M and Chen J: Models and mechanisms of vascular dementia. Exp Neurol. 272:97–108. 2015. View Article : Google Scholar : PubMed/NCBI
9	Khan A, Kalaria RN, Corbett A and Ballard C: Update on vascular dementia. J Geriatr Psychiatry Neurol. 29:281–301. 2016. View Article : Google Scholar : PubMed/NCBI
10	Murray ME, Meschia JF, Dickson DW and Ross OA: Genetics of vascular dementia. Minerva Psichiatr. 51:9–25. 2010.PubMed/NCBI
11	Travis J: New piece in alzheimer's puzzle. Science. 261:828–830. 1993. View Article : Google Scholar : PubMed/NCBI
12	Sun J, Tan L, Wang H, Tan M, Tan L, Li J, Xu W, Zhu X, Jiang T and Yu J: Genetics of vascular dementia: Systematic review and meta-analysis. J Alzheimers Dis. 46:611–629. 2015. View Article : Google Scholar : PubMed/NCBI
13	Jaenisch R and Bird A: Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet. 33 Suppl:S245–S254. 2003. View Article : Google Scholar
14	Fessele KL and Wright F: Primer in genetics and genomics, article 6: Basics of epigenetic control. Biol Res Nurs. 20:103–110. 2018. View Article : Google Scholar : PubMed/NCBI
15	Maloney B and Lahiri DK: Epigenetics of dementia: Understanding the disease as a transformation rather than a state. Lancet Neurol. 15:760–774. 2016. View Article : Google Scholar : PubMed/NCBI
16	Niculescu MD and Zeisel SH: Diet, methyl donors and DNA methylation: Interactions between dietary folate, methionine and choline. J Nutr. 132 8 Suppl:2333S–2335S. 2002. View Article : Google Scholar : PubMed/NCBI
17	Cong L, Jia J, Qin W, Ren Y and Sun Y: Genome-wide analysis of DNA methylation in an APP/PS1 mouse model of alzheimer's disease. Acta Neurol Belg. 114:195–206. 2014. View Article : Google Scholar : PubMed/NCBI
18	Sanchez-Mut JV and Gräff J: Epigenetic alterations in alzheimer's disease. Front Behav Neurosci. 9:3472015. View Article : Google Scholar : PubMed/NCBI
19	Jones PA: Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nat Rev Genet. 13:484–492. 2012. View Article : Google Scholar : PubMed/NCBI
20	Borgel J, Guibert S, Li Y, Chiba H, Schübeler D, Sasaki H, Forné T and Weber M: Targets and dynamics of promoter DNA methylation during early mouse development. Nat Genet. 42:1093–1100. 2010. View Article : Google Scholar : PubMed/NCBI
21	Valinluck V, Tsai H, Rogstad DK, Burdzy A, Bird A and Sowers LC: Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res. 32:4100–4108. 2004. View Article : Google Scholar : PubMed/NCBI
22	Farkas E, Luiten PG and Bari F: Permanent, bilateral common carotid artery occlusion in the rat: A model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev. 54:162–180. 2007. View Article : Google Scholar : PubMed/NCBI
23	Olton DS, Collison C and Werz MA: Spatial memory and radial arm maze performance of rats. Learn Motiv. 8:289–314. 1977. View Article : Google Scholar
24	Harris RA, Wang T, Coarfa C, Nagarajan RP, Hong C, Downey SL, Johnson BE, Fouse SD, Delaney A, Zhao Y, et al: Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications. Nat Biotechnol. 28:1097–1105. 2010. View Article : Google Scholar : PubMed/NCBI
25	Lan X, Adams C, Landers M, Dudas M, Krissinger D, Marnellos G, Bonneville R, Xu M, Wang J, Huang TH, et al: High resolution detection and analysis of CpG dinucleotides methylation using MBD-seq technology. PLoS One. 6:e222262011. View Article : Google Scholar : PubMed/NCBI
26	Serre D, Lee BH and Ting AH: MBD-isolated genome sequencing provides a high-throughput and comprehensive survey of DNA methylation in the human genome. Nucleic Acids Res. 38:391–399. 2010. View Article : Google Scholar : PubMed/NCBI
27	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-Delta Delta C (T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
28	Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC and Lempicki RA: DAVID: Database for annotation, visualization, and integrated discovery. Genome Biol. 4:P32003. View Article : Google Scholar : PubMed/NCBI
29	Sim YJ: Treadmill exercise alleviates impairment of spatial learning ability through enhancing cell proliferation in the streptozotocin-induced alzheimer's disease rats. J Exerc Rehabil. 10:81–88. 2014. View Article : Google Scholar : PubMed/NCBI
30	Hussein AM, Aher YD, Kalaba P, Aher NY, Dragačević V, Radoman B, Ilic M, Leban J, Beryozkina T, Ahmed ABMA, et al: A novel heterocyclic compound improves working memory in the radial arm maze and modulates the dopamine receptor D1R in frontal cortex of the sprague-dawley rat. Behav Brain Res. 332:308–315. 2017. View Article : Google Scholar : PubMed/NCBI
31	Huidobro C, Fernandez AF and Fraga MF: The role of genetics in the establishment and maintenance of the epigenome. Cell Mol Life Sci. 70:1543–1573. 2013. View Article : Google Scholar : PubMed/NCBI
32	Goldberg AD, Allis CD and Bernstein E: Epigenetics: A landscape takes shape. Cell. 128:635–638. 2007. View Article : Google Scholar : PubMed/NCBI
33	Klein H and De Jager PL: Uncovering the role of the methylome in dementia and neurodegeneration. Trends Mol Med. 22:687–700. 2016. View Article : Google Scholar : PubMed/NCBI
34	Ling C and Groop L: Epigenetics: A molecular link between environmental factors and type 2 diabetes. Diabetes. 58:2718–2725. 2009. View Article : Google Scholar : PubMed/NCBI
35	Yu B, Russanova VR, Gravina S, Hartley S, Mullikin JC, Ignezweski A, Graham J, Segars JH, DeCherney AH and Howard BH: DNA methylome and transcriptome sequencing in human ovarian granulosa cells links age-related changes in gene expression to gene body methylation and 3′-end GC density. Oncotarget. 6:3627–3643. 2015.PubMed/NCBI
36	Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M, Troakes C, Al-Sarraj S, Burrage J, Macdonald R, et al: Methylomic profiling implicates cortical deregulation of ANK1 in alzheimer's disease. Nat Neurosci. 17:1164–1170. 2014. View Article : Google Scholar : PubMed/NCBI
37	De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, Eaton ML, Keenan BT, Ernst J, McCabe C, et al: Alzheimer's disease: Early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci. 17:1156–1163. 2014. View Article : Google Scholar : PubMed/NCBI
38	Ma J, Sawai H, Ochi N, Matsuo Y, Xu D, Yasuda A, Takahashi H, Wakasugi T and Takeyama H: PTEN regulate angiogenesis through PI3K/akt/VEGF signaling pathway in human pancreatic cancer cells. Mol Cell Biochem. 331:161–171. 2009. View Article : Google Scholar : PubMed/NCBI
39	Waldner MJ and Neurath MF: Targeting the VEGF signaling pathway in cancer therapy. Expert Opin Ther Targets. 16:5–13. 2012. View Article : Google Scholar : PubMed/NCBI
40	Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, Desai S, Ferrara N, Nagy A, Roos KP and Iruela-Arispe ML: Autocrine VEGF signaling is required for vascular homeostasis. Cell. 130:691–703. 2007. View Article : Google Scholar : PubMed/NCBI
41	Ferrara N, Gerber H and LeCouter J: The biology of VEGF and its receptors. Nat Med. 9:669–676. 2003. View Article : Google Scholar : PubMed/NCBI
42	Franco CA and Li Z: SRF in angiogenesis: Branching the vascular system. Cell Adh Migr. 3:264–267. 2009. View Article : Google Scholar : PubMed/NCBI
43	Chai J, Jones MK and Tarnawski AS: Serum response factor is a critical requirement for VEGF signaling in endothelial cells and VEGF-induced angiogenesis. FASEB J. 18:1264–1266. 2004. View Article : Google Scholar : PubMed/NCBI
44	Ahmad S, Hewett PW, Wang P, Al-Ani B, Cudmore M, Fujisawa T, Haigh JJ, le Noble F, Wang L, Mukhopadhyay D and Ahmed A: Direct evidence for endothelial vascular endothelial growth factor receptor-1 function in nitric oxide-mediated angiogenesis. Circ Res. 99:715–722. 2006. View Article : Google Scholar : PubMed/NCBI
45	Morin-Brureau M, Lebrun A, Rousset MC, Fagni L, Bockaert J, de Bock F and Lerner-Natoli M: Epileptiform activity induces vascular remodeling and zonula occludens 1 downregulation in organotypic hippocampal cultures: Role of VEGF signaling pathways. J Neurosci. 31:10677–10688. 2011. View Article : Google Scholar : PubMed/NCBI
46	Dzietko M, Derugin N, Wendland M, Vexler Z and Ferriero D: Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke. Transl Stroke Res. 4:189–200. 2013. View Article : Google Scholar : PubMed/NCBI
47	Shimotake J, Derugin N, Wendland M, Vexler ZS and Ferriero DM: Vascular endothelial growth factor receptor-2 inhibition promotes cell death and limits endothelial cell proliferation in a neonatal rodent model of stroke. Stroke. 41:343–349. 2010. View Article : Google Scholar : PubMed/NCBI
48	Waltenberger J, Mayr U, Pentz S and Hombach V: Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation. 94:1647–1654. 1996. View Article : Google Scholar : PubMed/NCBI
49	Yang J, Liu H and Liu X: VEGF promotes angiogenesis and functional recovery in stroke rats. J Invest Surg. 23:149–155. 2010. View Article : Google Scholar : PubMed/NCBI