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http://dx.doi.org/10.3340/jkns.2021.0035

Identification of Differentially-Methylated Genes and Pathways in Patients with Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage  

Kim, Bong Jun (Institute of New Frontier Stroke Research, Hallym University College of Medicine)
Youn, Dong Hyuk (Institute of New Frontier Stroke Research, Hallym University College of Medicine)
Chang, In Bok (Department of Neurosurgery, Hallym University College of Medicine)
Kang, Keunsoo (Department of Microbiology, College of Science & Technology, Dankook University)
Jeon, Jin Pyeong (Department of Neurosurgery, Hallym University College of Medicine)
Publication Information
Journal of Korean Neurosurgical Society / v.65, no.1, 2022 , pp. 4-12 More about this Journal
Abstract
Objective : We reported the differentially methylated genes in patients with subarachnoid hemorrhage (SAH) using bioinformatics analyses to explore the biological characteristics of the development of delayed cerebral ischemia (DCI). Methods : DNA methylation profiles obtained from 40 SAH patients from an epigenome-wide association study were analyzed. Functional enrichment analysis, protein-protein interaction (PPI) network, and module analyses were carried out. Results : A total of 13 patients (32.5%) experienced DCI during the follow-up. In total, we categorized the genes into the two groups of hypermethylation (n=910) and hypomethylation (n=870). The hypermethylated genes referred to biological processes of organic cyclic compound biosynthesis, nucleobase-containing compound biosynthesis, heterocycle biosynthesis, aromatic compound biosynthesis and cellular nitrogen compound biosynthesis. The hypomethylated genes referred to biological processes of carbohydrate metabolism, the regulation of cell size, and the detection of a stimulus, and molecular functions of amylase activity, and hydrolase activity. Based on PPI network and module analysis, three hypermethylation modules were mainly associated with antigen-processing, Golgi-to-ER retrograde transport, and G alpha (i) signaling events, and two hypomethylation modules were associated with post-translational protein phosphorylation and the regulation of natural killer cell chemotaxis. VHL, KIF3A, KIFAP3, RACGAP1, and OPRM1 were identified as hub genes for hypermethylation, and ALB and IL5 as hub genes for hypomethylation. Conclusion : This study provided novel insights into DCI pathogenesis following SAH. Differently methylated hub genes can be useful biomarkers for the accurate DCI diagnosis.
Keywords
Subarachnoid hemorrhage; Intracranial aneurysm; DNA methylation; Computational biology; Epigenetics; Delayed cerebral ischemia;
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1 Dorsch NW, King MT : A review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage part I: incidence and effects. J Clin Neurosci 1 : 19-26, 1994   DOI
2 Francoeur CL, Mayer SA : Management of delayed cerebral ischemia after subarachnoid hemorrhage. Crit Care 20 : 277, 2016   DOI
3 Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, et al. : Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A 91 : 9700-9704, 1994   DOI
4 Kim BJ, Kim Y, Kim SE, Jeon JP : Study of correlation between Hp α1 expression of haptoglobin 2-1 and clinical course in aneurysmal subarachnoid hemorrhage. World Neurosurg 117 : e221-e227, 2018   DOI
5 Stamatovic SM, Phillips CM, Martinez-Revollar G, Keep RF, Andjelkovic AV : Involvement of epigenetic mechanisms and non-coding RNAs in blood-brain barrier and neurovascular unit injury and recovery after stroke. Front Neurosci 13 : 864, 2019   DOI
6 Duan W, Pan Y, Wang C, Wang Y, Zhao X, Wang Y, et al. : Risk factors and clinical impact of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: analysis from the China National Stroke Registry. Neuroepidemiology 50 : 128-136, 2018   DOI
7 Starke RM, Kim GH, Komotar RJ, Hickman ZL, Black EM, Rosales MB, et al : Endothelial nitric oxide synthase gene single-nucleotide polymorphism predicts cerebral vasospasm after aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab 28 : 1204-1211, 2008   DOI
8 Guinot A, Lehmann H, Wild PJ, Frew IJ : Combined deletion of Vhl, Trp53 and Kif3a causes cystic and neoplastic renal lesions. J Pathol 239 : 365-373, 2016   DOI
9 Kim BJ, Kim Y, Youn DH, Park JJ, Rhim JK, Kim HC, et al. : Genome-wide blood DNA methylation analysis in patients with delayed cerebral ischemia after subarachnoid hemorrhage. Sci Rep 10 : 11419, 2020   DOI
10 Chidambaran V, Zhang X, Martin LJ, Ding L, Weirauch MT, Geisler K, et al. : DNA methylation at the mu-1 opioid receptor gene (OPRM1) promoter predicts preoperative, acute, and chronic postsurgical pain after spine fusion. Pharmgenomics Pers Med 10 : 157-168, 2017
11 Endres M, Meisel A, Biniszkiewicz D, Namura S, Prass K, Ruscher K, et al. : DNA methyltransferase contributes to delayed ischemic brain injury. J Neurosci 20 : 3175-3181, 2000   DOI
12 Hamzei Moqaddam A, Ahmadi Musavi SM, Khademizadeh K : Relationship of opium dependency and stroke. Addict Health 1 : 6-10, 2009
13 Ieda M, Miyaoka T, Kawano K, Wake R, Inagaki T, Horiguchi J : May salivary alpha-amylase level be a useful tool for assessment of the severity of schizophrenia and evaluation of therapy? A case report. Case Rep Psychiatry 2012 : 747104, 2012   DOI
14 Kovacic MB, Myers JM, Wang N, Martin LJ, Lindsey M, Ericksen MB, et al. : Identification of KIF3A as a novel candidate gene for childhood asthma using RNA expression and population allelic frequencies differences. PLoS One 6 : e23714, 2011   DOI
15 McRonald FE, Morris MR, Gentle D, Winchester L, Baban D, Ragoussis J, et al. : CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma. Mol Cancer 8 : 31, 2009   DOI
16 Rowland MJ, Hadjipavlou G, Kelly M, Westbrook J, Pattinson KT : Delayed cerebral ischaemia after subarachnoid haemorrhage: looking beyond vasospasm. Br J Anaesth 109 : 315-329, 2012   DOI
17 Li X, Lin S, Chen X, Huang W, Li Q, Zhang H, et al. : The Prognostic value of serum cytokines in patients with acute ischemic stroke. Aging Dis 10 : 544-556, 2019   DOI
18 Kim BJ, Kim Y, Hong EP, Jeon JP, Yang JS, Choi HJ, et al. : Correlation between altered DNA methylation of intergenic regions of ITPR3 and development of delayed cerebral ischemia in patients with subarachnoid hemorrhage. World Neurosurg 130 : e449-e456, 2019   DOI
19 Kim H, Crago E, Kim M, Sherwood P, Conley Y, Poloyac S, et al. : Cerebral vasospasm after sub-arachnoid hemorrhage as a clinical predictor and phenotype for genetic association study. Int J Stroke 8 : 620-625, 2013   DOI
20 Babu MS, Kaul S, Dadheech S, Rajeshwar K, Jyothy A, Munshi A : Serum albumin levels in ischemic stroke and its subtypes: correlation with clinical outcome. Nutrition 29 : 872-875, 2013   DOI
21 Lei L, Mason S, Liu D, Huang Y, Marks C, Hickey R, et al. : Hypoxiainducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein. Mol Cell Biol 28 : 3790-3803, 2008   DOI
22 Kyadav K, Chaudhary HR, Gupta RC, Jain R, Yadav SR, Sharma S, et al. : Clinical profile and outcome of stroke in relation to glycaemic status of patients. J Indian Med Assoc 102 : 138-139, 142, 150, 2004
23 Martynov IuS, Shuvakhina NA : Carbohydrate metabolism disorders in stroke. Zh Nevropatol Psikhiatr Im S S Korsakova 79 : 1281-1288, 1979
24 Knutsson A, Bjorkbacka H, Duner P, Engstrom G, Binder CJ, Nilsson AH, et al. : Associations of interleukin-5 with plaque development and cardiovascular events. JACC Basic Transl Sci 4 : 891-902, 2019   DOI
25 Kurmi K, Haigis MC : Nitrogen metabolism in cancer and immunity. Trends Cell Biol 30 : 408-424, 2020   DOI
26 Lad SP, Hegen H, Gupta G, Deisenhammer F, Steinberg GK : Proteomic biomarker discovery in cerebrospinal fluid for cerebral vasospasm following subarachnoid hemorrhage. J Stroke Cerebrovasc Dis 21 : 30-41, 2012   DOI
27 Liu D, Zempleni J : Transcriptional regulation of the albumin gene depends on the removal of histone methylation marks by the FAD-dependent monoamine oxidase lysine-specific demethylase 1 in HepG2 human hepatocarcinoma cells. J Nutr 144 : 997-1001, 2014   DOI
28 Liu Y, Gu HY, Zhu J, Niu YM, Zhang C, Guo GL : Identification of Hub genes and key pathways associated with bipolar disorder based on weighted gene co-expression network analysis. Front Physiol 10 : 1081, 2019   DOI
29 Nikkola E, Laiwalla A, Ko A, Alvarez M, Connolly M, Ooi YC, et al. : Remote ischemic conditioning alters methylation and expression of cell cycle genes in aneurysmal subarachnoid hemorrhage. Stroke 46 : 2445-2451, 2015   DOI
30 Ott MO, Sperling L, Cassio D, Levilliers J, Sala-Trepat J, Weiss MC : Undermethylation at the 5' end of the albumin gene is necessary but not sufficient for albumin production by rat hepatoma cells in culture. Cell 30 : 825-833, 1982   DOI
31 Qureshi WT, O'Neal WT, Khodneva Y, Judd S, Safford MM, Muntner P, et al. : Association between opioid use and atrial fibrillation : the reasons for geographic and racial differences in stroke (REGARDS) study. JAMA Intern Med 175 : 1058-1060, 2015
32 Sang L, Wang XM, Xu DY, Zhao WJ : Bioinformatics analysis of aberrantly methylated-differentially expressed genes and pathways in hepatocellular carcinoma. World J Gastroenterol 24 : 2605-2616, 2018   DOI
33 Suarez JI, Martin RH, Calvillo E, Dillon C, Bershad EM, Macdonald RL, et al. : The albumin in subarachnoid hemorrhage (ALISAH) multicenter pilot clinical trial: safety and neurologic outcomes. Stroke 43 : 683-690, 2012   DOI
34 Zaina S, Heyn H, Carmona FJ, Varol N, Sayols S, Condom E, et al. : DNA methylation map of human atherosclerosis. Circ Cardiovasc Genet 7 : 692-700, 2014   DOI
35 Zhao W, Lei T, Li H, Sun D, Mo X, Wang Z, et al. : Macrophage-specific overexpression of interleukin-5 attenuates atherosclerosis in LDL receptor-deficient mice. Gene Ther 22 : 645-652, 2015   DOI
36 Samuelsson C, Howells T, Kumlien E, Enblad P, Hillered L, Ronne-Engstrom E : Relationship between intracranial hemodynamics and microdialysis markers of energy metabolism and glutamate-glutamine turnover in patients with subarachnoid hemorrhage. Clinical article. J Neurosurg 111 : 910-915, 2009   DOI
37 Pascual JM, Carceller F, Roda JM, Cerdan S : Glutamate, glutamine, and GABA as substrates for the neuronal and glial compartments after focal cerebral ischemia in rats. Stroke 29 : 1048-1056; discussion 1056-1057, 1998   DOI
38 Peyravian N, Dikici E, Deo S, Toborek M, Daunert S : Opioid antagonists as potential therapeutics for ischemic stroke. Prog Neurobiol 182 : 101679, 2019   DOI