精神分裂症病患與正常人之DNA甲基化網絡的差異

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李懿瑋(Yi-wei Lee) 查詢紙本館藏

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系統生物與生物資訊研究所

論文名稱

精神分裂症病患與正常人之DNA甲基化網絡的差異
(The difference of DNA methylation network between schizophrenic and normal individuals)

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摘要(中)

精神分裂症屬於complex disease之一，主要會造成病患無法區分虛實之間的差異，嚴重者將有危及生命的行為發生，但目前針對精神分裂症的相關研究，有許多假說相繼成立，包括：神經傳導素分泌失調、腦部發育不正常等，但仍無法明確地指出何種因素才是引發疾病的主要因子；故目前人類僅可藉由藥物阻斷特定神經傳導物質，以緩和病患發病的症狀。在此研究中我們採用不同於以往僅著重於研究基因序列的方式，反而以表觀基因體學研究方式為主。而分析數據主要來自精神分裂症病患與正常人兩組別，藉由微陣列偵測CpG island的甲基化程度，再將偵測到的數據，首先挑選出不含重複序列共7,843 個spots，接著選擇7,843 spots 當中甲基化程度差異大者前2,005個spots，此2,005 spots可作為分析觀察條件之一；另外，若僅以去除NA值為條件篩選7,843 spots，則可得到7,647 spots。所以在前述兩篩選條件中，分別可得2,005 spots與7,647 spots兩組基因，再利用計算partial correlation coefficient即可推測具甲基化程度相關性的基因對，以此為依據建立CpG island co-methylation network。接著再對各組網絡進行基本特性分析，而由我們分析結果得知，在病患所構成的網絡中不論在top 2,005 variable spots或是7,647 spots，其具關聯性的基因主要功能傾向以神經發育、訊號傳遞、DNA甲基化相關過程為主；但正常人所建立的網絡卻無此特徵。雖然藉由甲基化分析，仍無法確認甲基化程度的失常是否會影響腦中基因表現量，但我們分析結果可確定精神分裂症病患CpG islands甲基化程度的相關性比正常人還要密切，使得基因之間容易互相影響，導致基因在面對環境變化時缺少預防變異的機制，而增加基因失調的機率。

摘要(英)

Schizophrenia is a complex disease. It affects the most basic human processes of perception, emotion, and judgment. However, progress in schizophrenia has been slow. Previous researches have shown many contentions about pathogenic factors, including deregulated neurotransmitter, development of the brain, and genetic risk factors. But these studies have not identified a key factor which directly induces people suffering from schizophrenia. Now, people use drugs to treat schizophrenia despite studies can not provide clear understanding of the pathogenesis of the disease. In this research, we investigate the difference of DNA methylation networks between schizophrenia and normal persons. First, we selected 2,005 spots and 7,647 spots from microarray, consisting a total of 13,056 spots. In order to establish the DNA methylation networks, we calculated partial correlation coefficients between methylation patterns of CpG islands. Our results found that major gene functions of the networks, from either 2005 spots or 7647 spots from patients , involved neural development, signal transduction, and the process of DNA methylation. By contrast, no specific functions in the networks of normal persons were observed. These results revealed the stronger correlation of gene methylation patterns in patients than in normal persons. We suggest that genes in patients with schizophrenia, having the above properties, hold defect in handling environmental changes, and might raise the possibility of alterations in gene regulation.

關鍵字(中)

★ 精神分裂症
★ 網絡
★ 甲基化

關鍵字(英)

★ DNA methylation
★ network
★ schizophrenia

論文目次

目錄
中文摘要 ---------------------------------------------i
Abstract ---------------------------------------------ii
誌謝 ---------------------------------------------iii
目錄 ---------------------------------------------iv
圖目錄 ---------------------------------------------vii
表目錄 ---------------------------------------------viii
第一章緒論 --------------------------------------1
一、Epigenetics -------------------------------------1
二、DNA甲基化 -------------------------------------1
2-1 DNA甲基化機制 ----------------------------------1
2-1-1 甲基化狀態的維持(maintenance methylation)-----3
2-1-2 甲基化重新組合(de novo methylation) ----------3
2-2 DNA甲基化對於基因表現的影響---------------------5
2-2-1 甲基化CpG結合蛋白
(methyl CpG binding protiens， MBP)-----------6
2-3 組蛋白修飾---------------------------------------8
2-3-1 DNA甲基化和組蛋白修飾之關係------------------9
2-3-2 DNA 甲基化、組蛋白去乙醯化、組蛋白甲基化
三者之間的關係-------------------------------10
2-4 DNA甲基化抑制基因表達---------------------------11
三、Imprinting----------------------------------------13
3-1 銘印基因的重要性--------------------------------13
3-2 germ-line銘印基因的建立與維持-----------------14
3-2-1 擦去(Erasure)與建立---------------------------14
3-2-2 銘印基因的維持--------------------------------14
3-3 銘印基因的特性----------------------------------15
3-4 調控銘印基因表現的方法--------------------------16
3-5 X-inactivation----------------------------------19
四、精神分裂症(Schizophrenia)-------------------------20
4-1 基因表觀因子與人類疾病之關係---------------------20
4-2 表觀基因體和精神疾病-----------------------------21
4-3 精神分裂症---------------------------------------22
4-3-1 精神分裂症在神經病理上的發現------------------24
4-3-2 精神分裂症在基因體上的發現--------------------25
4-3-3 精神分裂症與表觀基因體的關係------------------28
五、研究動機------------------------------------------32
第二章研究方法---------------------------------------33
一、實驗樣品------------------------------------------33
二、歸一化(normalization)-----------------------------33
三、扣除M值為NA的基因---------------------------------34
四、計算M值標準差 -------------------------------------34
五、Rest數值的計算------------------------------------34
六、Partial Correlation Coefficients的計算------------34
七、網路特性分析--------------------------------------35
八、GO term檢定---------------------------------------37
第三章結果-------------------------------------------38
一、基因的篩選結果------------------------------------38
二、網絡的建立----------------------------------------39
三、網絡的結果與特性分析------------------------------40
3-1 網絡的組成--------------------------------------40
3-2 網絡degree的分布--------------------------------46
3-3 Clustering coefficient--------------------------48
3-4 Assortativity (同類性)--------------------------50
3-5 Module sizes的分布------------------------------52
四、篩選的spots在人類染色體位置的分布-----------------54
4-1 2,005 spots在人類染色體中的分布-----------------54
4-2 7,647 spots在人類染色體中的分布-----------------54
五、網絡modules 經GO term統計計算後結果----------------58
5-1 modules 的生物意義( 2,005spots組成的網絡)-------58
5-2 modules 的生物意義( 7,647spots組成的網絡)-------59
六、hubs的生物意義-------------------------------------59
6-1 網絡中前十名hubs的生物功能(2,005spots組成的網絡)-59
6-2 網絡中前十名hubs的生物功能(7,647spots組成的網絡)-60
七、7,674網絡各link的基因功能--------------------------60
7-1 正常人網絡中links的基因功能---------------------60
7-2 病患網絡中links的基因功能-----------------------61
第四章討論-------------------------------------------63
第五章結論-------------------------------------------65
第六章參考文獻---------------------------------------87
圖目錄
Fig. 1、基因甲基化修飾過程-----------------------------2
Fig. 2、Germ cell與受精後胚胎中，基因甲基化程度的變化關係
-----------------------------------------------4
Fig. 3、在cell cycle中MBD1利用組蛋白甲基化進行DNA甲基化修
飾過程-----------------------------------------7
Fig. 4、Igf2-H19基因ICR區域的甲基化修飾的建立與維持----18
Fig. 5、晶片spots篩選步驟------------------------------38
Fig. 6、non-overlapping spots--------------------------39
Fig. 7、2,005 spots甲基化程度相關性網絡----------------43
Fig. 8、7,647 spots甲基化程度相關性網絡----------------44
Fig. 9、random組別在2,005 spots與7,647 spots條件下的網絡
-----------------------------------------------45
Fig.10、degree distribution ---------------------------47
Fig.11、各degrees值所對應平均clustering coefficient值的分
布圖-------------------------------------------49
Fig.12、各degrees值所對應平均assortativity值的分布圖---51
Fig.13、Module sizes的分布-----------------------------53
Fig.14、篩選spots在人類染色體的分布--------------------55
Fig.15、2,005 spots網絡中帶有degrees的nodes在染色體中的位
置---------------------------------------------56
Fig.16、7,647 spots網絡中帶有degrees的nodes在染色體中的位
置---------------------------------------------57
表目錄
Table 1、各MBP酵素的組成與功能整理---------------------6
Table 2、各組partial correlation經檢定後符合限定門檻的
edges數---------------------------------------39
Table 3、網絡基本特性----------------------------------42
Table 4、正常人網絡modules在2,005個基因中有統計意義的GO
terms-----------------------------------------67
Table 5、病患網絡modules在2,005個基因中有統計意義的GO
terms-----------------------------------------70
Table 6、病患或正常人網絡modules在7,647個基因中有統計意義
的GO terms------------------------------------72
Table 7、2,005 spots網絡hubs的基因ID與基因名稱---------73
Table 8、7,647 spots網絡hubs的基因ID與基因名稱---------74
Table 9、正常人組別中7,647 spots組成網絡，其參與link的兩基
因對應基因功能--------------------------------77
Table 10、病人組別中7,647 spots組成網絡，其參與link的兩基
因對應生物功能--------------------------------86

參考文獻

參考文獻
［1］Issa, J.P.,“CpG-island methylation in aging and cancer”, Curr. Top. Microbiol. Immunol., Vol 249, pp.101-118, 2000.
［2］Wilson G.G. and N.E. Murray, “Restriction and modification systems”, Annu. Rev. Genet., Vol 25 , pp. 585–627, 1991.
［3］Hermann A., R. Goyal, and A. Jeltsch, “The Dnmt1 DNA-(cytosine-C5) – methyltransferase methylates DNA processively with high preference for hemimethylated target sites.” , J. Bio. Chem., Vol 279 , pp.48350-48359, 2004.
［4］Delaval K. and Robert F.,“Epigenetic regulation of mammalian genomic imprinting”, Current Opinion in Genetics & Development ,Vol.14, pp.188-195,2004
［5］Lei, H. et al. “De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. ”, Development , Vol 122, pp. 3195-3205, 1996.
［6］Okano, M., D.W. Bell, D.A. Haber, and E. Li, “DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.’’ ,Cell, Vol 99, pp.247-257, 1999.
［7］Jaenisch R. and A. Bird.,“Epigenetic regulation of gene expression : how the genome integrates intrinsic and environmental singals”,Nature, Vol. 33, pp.245 -254, 2003.
［8］Jones PL, et al. “Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.”, Nat. Genet., Vol 19, pp.187-191, 1998.
［9］Nan X, et al.“Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex .”, Nature ,Vol. 393 , pp.386-389 , 1998.
［10］Marisa S. Bartolomei and Shirley M. Tilghman,“Genomic imprinting in mammals”, Annu. Rev. Genet., Vol. 31,pp.493-525,1997.
［11］Simon, I. et al.“Asynchronous replication of imprinted genes is established in the gametes and maintained during development.”Nature ,Vol. 401, pp.929–932, 1999.
［12］Reik W., and W. Jorn,“Genomic imprinting : parental influence on the genome”, Nature, Vol 2,pp.21-32,2001.
［13］Hendrich B ,and Bird A., ‘‘Identification and characterization of a family of mammalian methyl-CpG binding proteins”, Mol Cell Biol., Vol. 18 , pp.6538- 6547,1998.
［14］Zhang Y., Ng H.H., and H. Erdjument-Bromage, et. al., “Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation ”, Gene Dev.,Vol. 13,No.15, pp.1924-1935, 1999.
［15］Kitsberg D., et. al.,“Allele-specific replication timing of imprinted gene regions” Nature, Vol.364, pp.459–63, 1993.
［16］Klose RJ., and AP. Bird,“Genomic DNA methylation: the mark and its mediators.”, Trends Biochem. Sci., Vol. 31, No.2,pp.89-97, 2006 .
［17］DeChiara TM, Robertson EJ, and Efstratiadis A., “Parental imprinting of the mouse insulin-like growth factor II gene” Cell, Vol. 64, pp.849–59,1991.
［18］Lerchner W,and Barlow DP.“Paternal repression of the imprinted mouse Igf2r locus occurs during implantation and is stable in all tissues of the post-implantation mouse embryo”, Mech Dev., Vol. 61, pp.141-9, 1997.
［19］Ekstrom TJ. et. al.,“Promoter-specific IGF2 imprinting status and its plasticity during human liver development”, Development, Vol.121, pp.309–316,1995.
［20］Pfeifer K. ,and Tilghman SM.,“Allelespecific gene expression in mammals: the curious case of the imprinted RNAs.”Genes Dev. ,Vol. 8, pp.1867–1874,1994.
［21］Okano, M., Bell, D.W., Haber, D.A., and Li, E. “DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.”,Cell, Vol.99, pp.247–257.1999.
［22］Bird A.,“DNA methyaltion patterns and epigenetic memory”,Genes and Dev.,Vol. 16, pp.6-21,2002.
［23］Rhee, I., Jair, K.W., Yen, R.W., Lengauer, C., Herman, J.G., Kinzler, K.W., Vogelstein, B., Baylin, S.B., and Schuebel, K.E. ,“CpG methylation is maintained in human cancer cells lacking DNMT1.”,Nature, Vol. 404 ,pp.1003–1007.2000.
［24］Horike, S. et al.“Targeted disruption of the human LIT1 locus defines a putative imprinting control element playing an essential role in Beckwith–Wiedemann syndrome”, Hum. Mol. Genet., Vol. 9, pp.2075–2083, 2000.
［25］Reik, W. et al.“Epigenetic reprogramming in mammalian development.”, Science, Vol. 293, pp.1089–1093 ,2001.
［26］Constancia, M. et al.,“Deletion of a silencer element in Igf2 results in loss of imprinting independent of H19”, Nature Genet. Vol. 26, pp.203–206, 2000.
［27］Schoenherr CJ., Levorse JM., and Tilghman SM.,“CTCF maintains differential methylation at the Igf2/H19 locus”, Nat Genet, Vol.33, pp.66-69. 2003.
［28］Huyen, Y. et al. ,“Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks.”, Nature, Vol. 432, pp. 406–411,2004.
［29］Maurer-Stroh, S. et al.,“The Tudor domain ‘Royal Family’: Tudor, plant Agenet, Chromo, PWWP and MBT domains.”,Trends Biochem. Sci. ,Vol. 28, pp. 69 –74 ,2003.
［30］Di Croce, L. et al.,“Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor.”, Science, Vol. 295, pp.1079–1082 ,2002.
［31］Delaval K, Feil R., “Epigenetic regulation of mammalian genomic imprinting.”, Curr Opin Genet Dev., Vol.14, No.2, pp.188-195, 2004.
［32］Clemson CM. et. al.,“XISTRNApaints the inactiveXchromosome at interphase: evidence for a novel RNA involved in nuclear/ chromosome structure.” J. Cell Biol., Vol. 132, pp.259–75, 1996.
［33］Gartler S.M. ,and M.A. Goldman, “X-Chromosome Inactivation”, Encyclopedia of Life Sciences, pp.3-6,2006.
［34］Peedicayil J. ,“The role of epigenetics in mental disorders.”, Indian J Med Res. ,Vol. 126, pp.105-111, 2007 .
［35］Kanellopoulou C. et al. ,“Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing.”Genes Dev., Vol. 19, pp.489–501,(2005)
［36］Andreu N. et. al.,“Wiskott-Aldrich syndrome in a feamale with skewed X-chromosome inactivation”, Blood Cell Mol Dis., Vol. 31,No.3,pp.332-337,2003.
［37］Fraga MF, Ballestar E, and Paz MF et al.“Epigenetic differences arise during the lifetime of monozygotic twins”, Proc Natl Acad Sci USA., Vol. 102, 10604–10609, 2005.
［38］Stuffrein-Roberts S, Joyce PR, and Kennedy MA.,“Role of epigenetics in mental disorders.” , Aust N Z J Psychiatry., Vol.42, No. 2, pp.97-107. 2008.
［39］Jeddeloh, J.A., Stokes, T.L., and Richards, E.J..,“Maintenance of genomic methylation requires a SW12/SNF2-like protein.” Nat. Genet., Vol. 22, pp. 94–97,1999.
［40］Petronis A., et. al., “Monozygotic twins exhibit numerous epigenetic differences: Clues to twin discordance?”, SchizophrBull, Vol. 29, pp.169-178, 2003.
［41］Aston C, Jiang L, and Sokolov BP., “Microarray analysis of postmortem temporal cortex from patients with schizophrenia.”, J Neurosci Res. ,Vol. 77 ,pp. 858-866, 2004.
［42］Yates T.D.,“Structures of SET domain proteins: protein lysine methyltransferase make their mark”, Cell, Vol. 111,pp.5-7,2002.
［43］West RL, Lee JM, and Maroun LE. “Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer’s disease patient”, J Mol Neurosci, Vol.6 , pp.141-146, 1995.
［44］Zegerman P. et. al., “Histone H3 lysine 4 methylation disrupts binding of nucleosome remodeling and deacetylase (NuRD) repressor complex.”, J Biol Chem., Vol. 277,pp.11621–11624,2002.
［45］Schumacher A, et. al.,“Microarray-based DNA methylation profiling: technology and applications”, Nucleic Acids Res., Vol. 34, pp. 528-542, 2006.
［46］Gottesman, I.I.,and Shields, J. , “Schizophrenia: The Epigenetic Puzzle”, Cambridge University Press, Cambridge, p275,1982.
［47］Schultz SH,Steven M.D.,and Cleveland G.S.,“Schizophrenia: a review.”, Am Fam Physician., Vol. 75,No. 12,pp. 1821-1829, 2007.
［48］Ng HH, and Bird A.“DNA methylation and chromatin modification.”, Curr Opin Genet Dev., Vol. 9, pp:158-63, 1999.
［49］Tamaru, H. and Selker, E.U.,“A histone H3 methyltransferase controls DNA methylation in Neurospora crassa.”, Nature, Vol 414, pp.227-283, 2001.
［50］Jackson, J.P. et. al., “Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase.”, Nature, Vol. 416 , pp.556-560, 2002.
［51］Bird A.P.,and Wolffe A.P.,“Methylation-induced repression — belts,braces, and chromatin.”, Cell, Vol. 99, pp.451-454, 1999.
［52］Antonova, E., Sharma, T., Morris, R., and Kumari, V. ,“The relationship between brain structure and neurocognition in schizophrenia: a selective review”, Schizophr. Res., Vol. 70, pp.117–145, 2004.
［53］Freitag M.,and Selker E.U.,“ Controlling DNA methylation: many roads to one modification.”, Curr. Opin. Genet Dev., Vol. 15, pp.191-199, 2005.
［54］Lehnertz B.,et. al.,“Suv39hmediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin.”, Curr. Biol., Vol. 13, pp.1192-1200, 2003.
［55］Fuks F., Hurd P.J., Deplus R., Kouzarides T.,“The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase.”, Nucleic Acids Res., Vol. 31,pp.2305-2312, 2003.
［56］Rea S., et. al.,“Regulation of chromatin structure by site-specific histone H3 methyltransferases.”, Nature, Vol. 406, pp.593-599, 2000.
［57］Lewis A, et. al.,“Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation.”, Nat. Genet., Vol. 36, pp.1291-1295, 2004.
［58］Singal R.,and Ginder G.D.”DNA methylation”, Blood , Vol. 12, pp.4059-4070,1999.
［59］Boyes J. ,and Bird A.,“DNA methylation inhibits transcription indirectlyvia a methyl-CpG binding protein.”, Cell , Vol. 64, p.1123, 1991.
［60］Boyes J. ,and Bird A.,“Repression of genes by DNA methylation depends on CpG density and promoter strength: Evidence for involvement of a methyl-CpG binding protein.”, EMBO J. , Vol. 11, p.327, 1992.
［61］Goldman-Rakic, P.S., “The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia.”, Biol. Psychiatry, Vol. 46, pp.650–661, 1999.
［62］Nan X., Campoy F.J. ,and Bird A.,“MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin.”, Cell, Vol. 88, p.471, 1997.
［63］Kass SU., Landsberger N. ,and Wolffe A.P.,“DNA methylation directs a time-dependent repression of transcription initiation.”, Curr Biol .,Vol. 7,p.157,1997.
［64］Garrick D., et al.,“Repeat-induced gene silencing in mammals”, Nature Genetics, Vol. 18, pp 56-59,1998.
［65］Wade PA.,“Methyl CpG-binding proteins and transcriptional repression.” , Bioessays , Vol.23,No.12,pp.1131-7,2001.
［66］Fuks F., “DNA methylation and histone modifications: teaming up to silence genes ”, Curr Opin Genet Dev., Vol. 15, No.5, pp:490-5, 2005.
［67］Geiman TM, and Robertson KD.,“Chromatin remodeling, histone modifications, and DNA methylation-how does it all fit together?”, J Cell Biochem., Vol. 87,No.2,pp:117-25.
［68］林潔、來茂德，「DNA甲基化、組蛋白去乙醯化與基因表達抑制」，臨床與實驗病理學雜誌，22(3),353-356頁，2006。
［69］Detich N, Theberge J, and Szyf M.“Promoter-specific activation and demethylation by MBD2/demethylase.”, J Biol Chem. ,Vol.39 ,pp:35791-3584 ,2002.
［70］田筱青、房靜遠，「組蛋白甲基化研究進展」，生物化學與生物物理進展，33(6),511-516頁，2006。
［71］Rose C.A., et al.,“Neurobiology of schizophernia”, neuron,Vol.52, pp.139-153, 2006.
［72］Wassink TH, Nopoulos P, Pietila J, Crowe RR, Andreasen NC. “NOTCH4 and the frontal lobe in schizophrenia”, Am J Med Genet B Neuropsychiatr Genet., Vol. 118, pp.1–7, 2003.
［73］Iritani S.,“Neuropathology of schizophrenia: A mini review”, Neuropathology, Vol. 27, pp.604-608, 2007.
［74］張積家，陸愛桃，「精神分裂症患者的腦結構及其認知功能損害」，中國臨床心理學雜誌，第十三卷，第四期，495頁，2005年。
［75］Turner, J.A.,et al., “Imaging phenotypes and genotypes in schizophrenia.”, Neuroinformatics, Vol.4, pp:21-49,2006.
［76］Kato C. et al., “Molecular genetic studies of schizophrenia: challenges and insights.” , Neurosci Res., Vol. 43, No.4, pp:295-304, 2002.
［77］Arnold, S.E., Talbot, K., and Hahn, C.G., “Neurodevelopment, neuroplasticity, and new genes for schizophrenia. Prog.”, Brain Res., Vol. 147, pp.319–345, 2005.
［78］Parasad S. et al,“Molecular genetics of schizophrenia：past, present and future”, J. Biosci., Vol. 27, No. 1, 2002.
［79］Seeman P, Kapur S.,“Schizophrenia: more dopamine, more D2 receptors”, Proc Natl, Acad Sci USA, Vol. 97, pp.7673-7675, 2000.
［80］Collier DA, Li T., “The genetics of schizophrenia: glutamate not dopamine?”, Eur J Pharmacol. ,Vol. 480, pp.177-184, 2003.
［81］Undine E.,“Molecular mechanism of Schizophrenia”, Cell Physiol Biochem, Vol.20, pp.687-702,2007.
［82］Meisenzahl E.M., et. al., “The role of dopamine for the pathophysiology of schizophrenia”, International Review of Psychiatry, Vol.19, No.4, pp.337–345, 2007.
［83］Vandenberg D J., et. al.,“Human dopamine transporter gene (DAT1) maps to chromosome 5p15?3 and displays a VNTR”, Genomics, Vol. 14, pp.1104–1106, 1992.
［84］Arora R. C. and Meltzer H. Y., “Serotonin2 (5HT2) receptor binding in the frontal cortex of schizophrenic patients”,J. Neural. Trans., Vol. 85, pp.19–29, 1991.
［85］Joyce J N., et. al., “Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics”, Neuropsychopharmacology, Vol. 8, pp.315–336, 1993.
［86］Johnson JW ,and Ascher P.,“Glycine potentiates the NMDA response in cultured mouse brain neurons.”, Nature, Vol.325, pp.529-31, 1987.
［87］Takai H., et al.,“NMDA-induced apoptosis in the developing rat brain”, Exp Toxicol Pathol., Vol. 55 ,pp.33-37, 2003.
［88］Lang U.E. et al., “Molecular mechanisms of schizophrenia.”, Cell Physiol Biochem., Vol. 20, No. 6, pp.687-702, 2007.
［89］Petronis A, Paterson A.D. and Kennedy JL. , “Schizophrenia:An Epigenetic Puzzle”, Schizophr. Bull., Vol. 25, pp. 639–655, 1999.
［90］Franklin G.C., Adam G.I., and Ohlsson R., “Genomic imprinting and mammalian development”, Placenta, Vol.17, pp.3-14, 1996.
［91］Battle Y L, et. al., “Seasonality and infectious disease in schizophrenia: the birth hypothesis revisited”, J. Psychiatr. Res., Vol. 33, pp.501–509, 1999.
［92］O’Reilly R.L. and Singh SM.,“Retroviruses and schizophrenia revisited”, Am. J. Med. Genet.,Vol. 67 pp.19–24, 1996.
［93］Petronis A.,“The genes for major psychosis: aberrant sequence or regulation?”, Neuropsychopharmacology, Vol.23, No.1, pp.1-12, 2000.
［94］Bunzel R, et al.,“Polymorphic imprinting of the serotonin-2A (5-HT2A) receptor gene in human adult brain.” , Brain Res Mol Brain Res, Vol. 59, pp.90–92, 1998.
［95］Flight M.H.,“Epigenetics:Methylation and schizophrenia”, Nature Reviews Neuroscience , Vol. 8, pp.910-911, 2007.
［96］Dugs J.C. et al.,“Functional Genomic Analysis of Oligodendrocyte Differentiation”, The Journal of Neuroscience , Vol. 26, pp.10967-10983, 2006.
［97］Adrian Bird, ‘‘Introduction perceptions of epigenetics’’, Nature, Vol. 447, pp. 396-398, 2007.
［98］Sharma R.P.,“Schizophrenia, epigenetics and ligand-activated nuclear receptors:a framework for chromatin therapeutics”, Schizophr Res., Vol. 72, pp. 79-90.
［99］Schafer J. and Korbinian S.,“An empirical Bayes appraoch to inferring large-scale gene association networks”, Systems biology, Vol. 21, no.6, pp.754-764, 2004.
［100］Alexa A.,Jorg R., and Thomas L.,“Imrpoved scoring of functional groups from gene expression data by decorrelating GO graph structure”, Bioinformatics, Vol. 22, no. 13,pp.1600-1607,2006.
［101］Newman M. E. J., “Modularity and community structure in networks”, PNAS., Vol. 103, pp.8577-8582, 2006.
［102］Kimberly D. et al.,“DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons”, PLoS ONE, Vol. 19, pp.e895, 2007.
［103］Connor C.M. and S. Akbarian, “DNA methylation changes in schizophrenia and bipolar disorder.”, Epigenetics , Vol. 3, pp.55-58, 2008.
［104］Mill J. et al.,“Epigenomic profiling reveals DNA-methylation changes associated with major psychosis”, Am J Hum Genet, Vol. 82, pp.696-711, 2008.
［105］Pastor-Satorras, et al., “Dynamical and Correlation Properties of the Internet”, Phys. Rev. Lett., Vol. 87, 2001.

指導教授

王孫崇(Sun-chong Wang)

審核日期

2008-7-14

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