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Volumn 6, Issue 8, 2011, Pages 1012-1020

Establishment of paternal allele-specific DNA methylation at the imprinted mouse GTl2 locus

Author keywords

DNA methylation; Epigenetics; Genomic imprinting; Gtl2; Secondary DMR

Indexed keywords

CYCLIN DEPENDENT KINASE INHIBITOR 1C; DNA; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR GTL2; UNCLASSIFIED DRUG;

EID: 79961244052     PISSN: 15592294     EISSN: 15592308     Source Type: Journal    
DOI: 10.4161/epi.6.8.16075     Document Type: Article
Times cited : (30)

References (50)
  • 1
    • 0344393087 scopus 로고    scopus 로고
    • Genomic imprinting: Intricacies of epigenetic regulation in clusters
    • Verona RI, Mann MRW, Bartolomei MS. Genomic imprinting: intricacies of epigenetic regulation in clusters. Annu Rev Cell Dev Biol 2003; 19:237-59
    • (2003) Annu Rev Cell Dev Biol , vol.19 , pp. 237-259
    • Verona, R.I.1    Mann, M.R.W.2    Bartolomei, M.S.3
  • 2
    • 0035839126 scopus 로고    scopus 로고
    • Epigenetic reprogramming in mammalian development
    • Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science 2001; 293:1089-93
    • (2001) Science , vol.293 , pp. 1089-1093
    • Reik, W.1    Dean, W.2    Walter, J.3
  • 3
  • 4
    • 39049093762 scopus 로고    scopus 로고
    • Regulation of imprinting in clusters: Noncoding RNAs versus imsulators
    • Wan LB, Bartolomei MS. Regulation of imprinting in clusters: noncoding RNAs versus imsulators. Adv Genet 2008; 61:207-23
    • (2008) Adv Genet , vol.61 , pp. 207-223
    • Wan, L.B.1    Bartolomei, M.S.2
  • 5
    • 0030802395 scopus 로고    scopus 로고
    • A 5' 2-kilobase- pair region of the imprinted mouse H19 gene exhibits exclusive paternal methylation throughout development
    • Tremblay KD, Duran KL, Bartolomei MS. A 5' 2-kilobase- pair region of the imprinted mouse H19 gene exhibits exclusive paternal methylation throughout development. Mol Cell Biol 1997; 17:4322-9
    • (1997) Mol Cell Biol , vol.17 , pp. 4322-4329
    • Tremblay, K.D.1    Duran, K.L.2    Bartolomei, M.S.3
  • 6
    • 0036151866 scopus 로고    scopus 로고
    • Epigenetic analysis of the Dlk1- Gtl2 imprinted domain on mouse chromosome 12: Implications for imprinting control from comparison with Igf2-H19
    • Takada S, Paulsen M, Tevendale M, Tsai CE, Kelsey G, Cattanach BM, et al. Epigenetic analysis of the Dlk1- Gtl2 imprinted domain on mouse chromosome 12: implications for imprinting control from comparison with Igf2-H19. Hum Mol Genet 2002; 11:77-86
    • (2002) Hum Mol Genet , vol.11 , pp. 77-86
    • Takada, S.1    Paulsen, M.2    Tevendale, M.3    Tsai, C.E.4    Kelsey, G.5    Cattanach, B.M.6
  • 7
    • 0032053874 scopus 로고    scopus 로고
    • A methylation imprint mark in the mouse imprinted gene Grf1/Cdc25Mm locus shares a common feature with the U2afbp-rs gene: An association with a short tandem repeat and a hypermethylated region
    • Shibata H, Yoda Y, Kato R, Ueda T, Kamiya M, Hiraiwa N, et al. A methylation imprint mark in the mouse imprinted gene Grf1/Cdc25Mm locus shares a common feature with the U2afbp-rs gene: an association with a short tandem repeat and a hypermethylated region. Genomics 1998; 49:30-7
    • (1998) Genomics , vol.49 , pp. 30-37
    • Shibata, H.1    Yoda, Y.2    Kato, R.3    Ueda, T.4    Kamiya, M.5    Hiraiwa, N.6
  • 8
    • 64149106282 scopus 로고    scopus 로고
    • Identification of the mouse paternally expressed imprinted gene Zdbf2 on chromosome 1 and its imprinted human homolog ZDBF2 on chromosome 2
    • Kobayashi H, Yamada K, Morita S, Hiura H, Fukuda A, Kagami M, et al. Identification of the mouse paternally expressed imprinted gene Zdbf2 on chromosome 1 and its imprinted human homolog ZDBF2 on chromosome 2. Genomics 2009; 93:461-72
    • (2009) Genomics , vol.93 , pp. 461-472
    • Kobayashi, H.1    Yamada, K.2    Morita, S.3    Hiura, H.4    Fukuda, A.5    Kagami, M.6
  • 9
    • 0030886796 scopus 로고    scopus 로고
    • Structure of the imprinted mouse Snrpn gene and establishment of its parental-specific methylation pattern
    • Shemer R, Birger Y, Riggs AD, Razin A. Structure of the imprinted mouse Snrpn gene and establishment of its parental-specific methylation pattern. Proc Natl Acad Sci USA 1997; 94:10267-72
    • (1997) Proc Natl Acad Sci USA , vol.94 , pp. 10267-10272
    • Shemer, R.1    Birger, Y.2    Riggs, A.D.3    Razin, A.4
  • 11
  • 12
    • 0036333103 scopus 로고    scopus 로고
    • Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice
    • Hata K, Okano M, Lei H, Li E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 2002; 129:1983-93
    • (2002) Development , vol.129 , pp. 1983-1993
    • Hata, K.1    Okano, M.2    Lei, H.3    Li, E.4
  • 13
    • 3042584653 scopus 로고    scopus 로고
    • Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting
    • Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, et al. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 2004; 429:900-3
    • (2004) Nature , vol.429 , pp. 900-903
    • Kaneda, M.1    Okano, M.2    Hata, K.3    Sado, T.4    Tsujimoto, N.5    Li, E.6
  • 14
    • 7944230369 scopus 로고    scopus 로고
    • Methylation at mouse Cdkn1c is acquired during postimplantation development and functions to maintain imprinted expression
    • Bhogal B, Arnaudo A, Dymkowski A, Best A, Davis TL. Methylation at mouse Cdkn1c is acquired during postimplantation development and functions to maintain imprinted expression. Genomics 2004; 84:961-70
    • (2004) Genomics , vol.84 , pp. 961-970
    • Bhogal, B.1    Arnaudo, A.2    Dymkowski, A.3    Best, A.4    Davis, T.L.5
  • 15
    • 0035102797 scopus 로고    scopus 로고
    • Establishment and maintenance of DNA methylation patterns in mouse Ndn: Implications for maintenance of imprinting in target genes of the imprinting center
    • Hanel M, Wevrick R. Establishment and maintenance of DNA methylation patterns in mouse Ndn: implications for maintenance of imprinting in target genes of the imprinting center. Mol Cell Biol 2001; 21:2384-92
    • (2001) Mol Cell Biol , vol.21 , pp. 2384-2392
    • Hanel, M.1    Wevrick, R.2
  • 16
    • 0031844688 scopus 로고    scopus 로고
    • Multiple mechanisms regulate imprinting of the mouse distal chromosome 7 gene cluster
    • Caspary T, Cleary MA, Baker CC, Guan X, Tilghman SM. Multiple mechanisms regulate imprinting of the mouse distal chromosome 7 gene cluster. Mol Cell Biol 1998; 18:3466-74
    • (1998) Mol Cell Biol , vol.18 , pp. 3466-3474
    • Caspary, T.1    Cleary, M.A.2    Baker, C.C.3    Guan, X.4    Tilghman, S.M.5
  • 17
    • 33846028236 scopus 로고    scopus 로고
    • Allele-specific histone modification regulate expression of the Dlk1-Gtl2 imprinted domain
    • Carr MS, Yevtodiyenko A, Schmidt CL, Schmidt JV. Allele-specific histone modification regulate expression of the Dlk1-Gtl2 imprinted domain. Genomics 2007; 89:280-90
    • (2007) Genomics , vol.89 , pp. 280-290
    • Carr, M.S.1    Yevtodiyenko, A.2    Schmidt, C.L.3    Schmidt, J.V.4
  • 18
    • 33846972618 scopus 로고    scopus 로고
    • Differential histone modifications mark mouse imprinting control regions during spermatogenesis
    • Delaval K, Govin J, Cerqueira F, Rousseaux S, Khochbin S, Feil R. Differential histone modifications mark mouse imprinting control regions during spermatogenesis. EMBO J 2007; 26:720-9
    • (2007) EMBO J , vol.26 , pp. 720-729
    • Delaval, K.1    Govin, J.2    Cerqueira, F.3    Rousseaux, S.4    Khochbin, S.5    Feil, R.6
  • 19
    • 0037011058 scopus 로고    scopus 로고
    • Allele-specific histone lysine methylation marks regulatory regions at imprinted mouse genes
    • Fournier C, Goto Y, Ballestar E, Delaval K, Hever AM, Esteller M, et al. Allele-specific histone lysine methylation marks regulatory regions at imprinted mouse genes. EMBO J 2002; 21:6560-70
    • (2002) EMBO J , vol.21 , pp. 6560-6570
    • Fournier, C.1    Goto, Y.2    Ballestar, E.3    Delaval, K.4    Hever, A.M.5    Esteller, M.6
  • 20
    • 37549006834 scopus 로고    scopus 로고
    • The transcriptional status but not the imprinting control region determines allele-specific histone modifications at the imprinted H19 locus
    • Verona RI, Thorvaldsen JL, Reese KJ, Bartolomei MS. The transcriptional status but not the imprinting control region determines allele-specific histone modifications at the imprinted H19 locus. Mol Cell Biol 2008; 28:71-82
    • (2008) Mol Cell Biol , vol.28 , pp. 71-82
    • Verona, R.I.1    Thorvaldsen, J.L.2    Reese, K.J.3    Bartolomei, M.S.4
  • 21
    • 0034699324 scopus 로고    scopus 로고
    • Delta-like and Gtl2 are reciprocally expressed, differentially methylated linked imprinted genes on mouse chromosome 12
    • Takada S, Tevendale M, Baker J, Georgiades P, Campbell E, Freeman T, et al. Delta-like and Gtl2 are reciprocally expressed, differentially methylated linked imprinted genes on mouse chromosome 12. Curr Biol 2000; 10:1135-8
    • (2000) Curr Biol , vol.10 , pp. 1135-1138
    • Takada, S.1    Tevendale, M.2    Baker, J.3    Georgiades, P.4    Campbell, E.5    Freeman, T.6
  • 23
    • 0036856353 scopus 로고    scopus 로고
    • Analysis of candidate imprinted genes linked to Dlk1- Gtl2 using a congenic mouse line
    • Yevtodiyenko A, Carr MS, Patel N, Schmidt JV. Analysis of candidate imprinted genes linked to Dlk1- Gtl2 using a congenic mouse line. Mamm Genome 2002; 13:633-8
    • (2002) Mamm Genome , vol.13 , pp. 633-638
    • Yevtodiyenko, A.1    Carr, M.S.2    Patel, N.3    Schmidt, J.V.4
  • 25
    • 84887212367 scopus 로고    scopus 로고
    • At least ten genes define the imprinted Dlk1- Dio3 cluster on mouse chromosome 12qF1
    • Hagan JP, O'Neill BL, Stewart CL, Kozlov SV, Croce CM. At least ten genes define the imprinted Dlk1- Dio3 cluster on mouse chromosome 12qF1. PLoS One 2009; 4:4352
    • (2009) PLoS One , vol.4 , pp. 4352
    • Hagan, J.P.1    O'Neill, B.L.2    Stewart, C.L.3    Kozlov, S.V.4    Croce, C.M.5
  • 26
    • 0042856381 scopus 로고    scopus 로고
    • Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12
    • Lin SP, Youngson N, Takada S, Seitz H, Reik W, Paulsen M, et al. Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12. Nat Genet 2003; 35:97-102
    • (2003) Nat Genet , vol.35 , pp. 97-102
    • Lin, S.P.1    Youngson, N.2    Takada, S.3    Seitz, H.4    Reik, W.5    Paulsen, M.6
  • 27
    • 7944221225 scopus 로고    scopus 로고
    • Timing of establishment of paternal methylation imprints in the mouse
    • Li JY, Lees-Murdock DJ, Xu GL, Walsh CP. Timing of establishment of paternal methylation imprints in the mouse. Genomics 2004; 84:952-60
    • (2004) Genomics , vol.84 , pp. 952-960
    • Li, J.Y.1    Lees-Murdock, D.J.2    Xu, G.L.3    Walsh, C.P.4
  • 28
    • 34548705374 scopus 로고    scopus 로고
    • Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse
    • Kato Y, Kaneda M, Hata K, Kumaki K, Hisano M, Kohara Y, et al. Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse. Hum Mol Genet 2007; 16:2272-80
    • (2007) Hum Mol Genet , vol.16 , pp. 2272-2280
    • Kato, Y.1    Kaneda, M.2    Hata, K.3    Kumaki, K.4    Hisano, M.5    Kohara, Y.6
  • 29
    • 0023119242 scopus 로고
    • Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development
    • Monk M, Boubelik M, Lehnert S. Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development 1987; 99:371-82
    • (1987) Development , vol.99 , pp. 371-382
    • Monk, M.1    Boubelik, M.2    Lehnert, S.3
  • 31
    • 0036145567 scopus 로고    scopus 로고
    • Dynamic reprogramming of DNA methylation in the early mouse embryo
    • Santos F, Hendrich B, Reik W, Dean W. Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol 2002; 241:172-82
    • (2002) Dev Biol , vol.241 , pp. 172-182
    • Santos, F.1    Hendrich, B.2    Reik, W.3    Dean, W.4
  • 32
    • 0031779540 scopus 로고    scopus 로고
    • The mouse Gtl2 gene is differentially expressed during embryonic development, encodes multiple alternatively spliced transcripts, and may act as an RNA
    • Schuster-Gossler K, Bilinski P, Sado T, Ferguson-Smith A, Gossler A. The mouse Gtl2 gene is differentially expressed during embryonic development, encodes multiple alternatively spliced transcripts, and may act as an RNA. Dev Dyn 1998; 212:214-28
    • (1998) Dev Dyn , vol.212 , pp. 214-228
    • Schuster-Gossler, K.1    Bilinski, P.2    Sado, T.3    Ferguson-Smith, A.4    Gossler, A.5
  • 33
    • 0037385473 scopus 로고    scopus 로고
    • Alternative splicing and imprinting control of the Meg3/Gtl2-Dlk1 locus in mouse embryos
    • Croteau S, Charron MC, Latham KE, Naumova AK. Alternative splicing and imprinting control of the Meg3/Gtl2-Dlk1 locus in mouse embryos. Mamm Genome 2003; 14:231-41
    • (2003) Mamm Genome , vol.14 , pp. 231-241
    • Croteau, S.1    Charron, M.C.2    Latham, K.E.3    Naumova, A.K.4
  • 34
    • 0021237658 scopus 로고
    • Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis
    • Surani MAH, Barton SC, Norris ML. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 1984; 308:548-50
    • (1984) Nature , vol.308 , pp. 548-550
    • Surani, M.A.H.1    Barton, S.C.2    Norris, M.L.3
  • 35
    • 0021139084 scopus 로고
    • Completion of mouse embryogenesis requires both the maternal and paternal genomes
    • McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 1984; 37:179-83
    • (1984) Cell , vol.37 , pp. 179-183
    • McGrath, J.1    Solter, D.2
  • 36
    • 22844457491 scopus 로고    scopus 로고
    • DNA methylation and human disease
    • Robertson KD. DNA methylation and human disease. Nat Rev Genet 2005; 6:597-610
    • (2005) Nat Rev Genet , vol.6 , pp. 597-610
    • Robertson, K.D.1
  • 37
    • 0033694804 scopus 로고    scopus 로고
    • Parental origin-specific developmental defects in mice with uniparental disomy for chromosome 12
    • Georgiades P, Watkins M, Surani MA, Ferguson-Smith AC. Parental origin-specific developmental defects in mice with uniparental disomy for chromosome 12. Development 2000; 127:4719-28
    • (2000) Development , vol.127 , pp. 4719-4728
    • Georgiades, P.1    Watkins, M.2    Surani, M.A.3    Ferguson-Smith, A.C.4
  • 38
    • 0035128059 scopus 로고    scopus 로고
    • Breakpoint mapping positions the callipyge gene within a 450-kilobase chromosome segment containing the DLK1 and GTL2 genes
    • Berghmans S, Segers K, Shay T, Georges M, Cockett N, Charlier C. Breakpoint mapping positions the callipyge gene within a 450-kilobase chromosome segment containing the DLK1 and GTL2 genes. Mamm Genome 2001; 12:183-5
    • (2001) Mamm Genome , vol.12 , pp. 183-185
    • Berghmans, S.1    Segers, K.2    Shay, T.3    Georges, M.4    Cockett, N.5    Charlier, C.6
  • 39
    • 38649135702 scopus 로고    scopus 로고
    • Deletions and epimutations affecting the human 14q32
    • 2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes
    • Kagami M, Sekita Y, Nishimura G, Irie M, Kato F, Okada M, et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat Genet 2008; 40:237-42
    • (2008) Nat Genet , vol.40 , pp. 237-242
    • Kagami, M.1    Sekita, Y.2    Nishimura, G.3    Irie, M.4    Kato, F.5    Okada, M.6
  • 40
    • 33645216984 scopus 로고    scopus 로고
    • Regulated expression of two sets of paternally imprinted genes is necessary for mouse parthenogenetic development to term
    • Wu Q, Kumagai T, Kawahara M, Ogawa H, Hiura H, Obata Y, et al. Regulated expression of two sets of paternally imprinted genes is necessary for mouse parthenogenetic development to term. Reprod 2006; 131:481-8
    • (2006) Reprod , vol.131 , pp. 481-488
    • Wu, Q.1    Kumagai, T.2    Kawahara, M.3    Ogawa, H.4    Hiura, H.5    Obata, Y.6
  • 41
    • 0036318227 scopus 로고    scopus 로고
    • Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity
    • Moon YS, Smas CM, Lee K, Villena JA, Kim KH, Yun EJ, et al. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Mol Cell Biol 2008; 22:5585-92
    • (2008) Mol Cell Biol , vol.22 , pp. 5585-5592
    • Moon, Y.S.1    Smas, C.M.2    Lee, K.3    Villena, J.A.4    Kim, K.H.5    Yun, E.J.6
  • 42
    • 38649091005 scopus 로고    scopus 로고
    • Role of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placenta
    • Sekita Y, Wagatsuma H, Nakamura K, Ono R, Kagami M, Wakisaka N, et al. Role of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placenta. Nat Genet 2008; 40:243-8
    • (2008) Nat Genet , vol.40 , pp. 243-248
    • Sekita, Y.1    Wagatsuma, H.2    Nakamura, K.3    Ono, R.4    Kagami, M.5    Wakisaka, N.6
  • 43
    • 65449117188 scopus 로고    scopus 로고
    • Deletion of Gtl2, imprinted non-coding RNA, with its differentially methylated region induces lethal parent-origin-dependent defects in mice
    • Takahashi N, Okamoto A, Kobayashi R, Shirai M, Obata Y, Ogawa H, et al. Deletion of Gtl2, imprinted non-coding RNA, with its differentially methylated region induces lethal parent-origin-dependent defects in mice. Hum Mol Genet 2009; 18:1879-88
    • (2009) Hum Mol Genet , vol.18 , pp. 1879-1888
    • Takahashi, N.1    Okamoto, A.2    Kobayashi, R.3    Shirai, M.4    Obata, Y.5    Ogawa, H.6
  • 44
    • 77955744813 scopus 로고    scopus 로고
    • Activation of paternally expressed genes and perinatal death caused by deletion of the Gtl2 gene
    • Zhou Y, Cheunsuchon P, Nakayama Y, Lawlor MW, Zhong Y, Rice KA, et al. Activation of paternally expressed genes and perinatal death caused by deletion of the Gtl2 gene. Development 2010; 137:2643-52
    • (2010) Development , vol.137 , pp. 2643-2652
    • Zhou, Y.1    Cheunsuchon, P.2    Nakayama, Y.3    Lawlor, M.W.4    Zhong, Y.5    Rice, K.A.6
  • 47
    • 0027378582 scopus 로고
    • Role for DNA methylation in genomic imprinting
    • Li E, Beard C, Jaenisch R. Role for DNA methylation in genomic imprinting. Nature 1993; 366:362-5
    • (1993) Nature , vol.366 , pp. 362-365
    • Li, E.1    Beard, C.2    Jaenisch, R.3
  • 48
    • 0027400888 scopus 로고
    • Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal
    • Stöger R, Kubicka P, Liu CG, Kafri T, Razin A, Cedar H, et al. Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell 1993; 73:61-71
    • (1993) Cell , vol.73 , pp. 61-71
    • Stöger, R.1    Kubicka, P.2    Liu, C.G.3    Kafri, T.4    Razin, A.5    Cedar, H.6
  • 49
    • 77954156503 scopus 로고    scopus 로고
    • The IG-DMR and the MEG3-DMR at human chromosome 14q32.2: Hierarchical interaction and distinct functional properties as imprinting control centers
    • Kagami M, O'Sullivan MJ, Green AJ, Watabe Y, Arisaka O, Masawa N, et al. The IG-DMR and the MEG3-DMR at human chromosome 14q32.2: hierarchical interaction and distinct functional properties as imprinting control centers. PLOS Genet 2010; 6:1-13
    • (2010) PLOS Genet , vol.6 , pp. 1-13
    • Kagami, M.1    O'Sullivan, M.J.2    Green, A.J.3    Watabe, Y.4    Arisaka, O.5    Masawa, N.6
  • 50
    • 69949109915 scopus 로고    scopus 로고
    • Differential methylation persists at the mouse Rasgrf1 DMR in tissues displaying monoallelic and biallelic expression
    • Dockery L, Gerfen J, Harview C, Rahn-Lee C, Horton R, Park Y, et al. Differential methylation persists at the mouse Rasgrf1 DMR in tissues displaying monoallelic and biallelic expression. Epigenetics 2009; 4:241-7
    • (2009) Epigenetics , vol.4 , pp. 241-247
    • Dockery, L.1    Gerfen, J.2    Harview, C.3    Rahn-Lee, C.4    Horton, R.5    Park, Y.6


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.